Piperidine urea derivatives

ABSTRACT

Compounds of the formula I 
                         
in which R 1 -R 3  have the meanings indicated in Claim  1,  
 
are inhibitors of Tankyrase, and can be employed, inter alia, for the treatment of diseases such as cancer, cardiovascular diseases, central nervous system injury and different forms of inflammation.

BACKGROUND OF THE INVENTION

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

The present invention relates to piperidine urea derivatives whichinhibit the activity of Tankyrases (TANKs) andpoly(ADP-ribose)polymerase PARP-1. The compounds of this invention aretherefore useful in treating diseases such as cancer, multiplesclerosis, cardiovascular diseases, central nervous system injury anddifferent forms of inflammation. The present invention also providesmethods for preparing these compounds, pharmaceutical compositionscomprising these compounds, and methods of treating diseases utilizingpharmaceutical compositions comprising these compounds.

The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) is a member ofthe PARP enzyme family. This growing family of enzymes consist of PARPssuch as, for example: PARP-1, PARP-2, PARP-3 and Vault-PARP; andTankyrases (TANKs), such as, for example: TANK-1 and TANK-2. PARP isalso referred to as poly(adenosine 5′-diphospho-ribose) polymerase orPARS (poly(ADP-ribose) synthetase).

TANK-1 seems to be required for the polymerization of mitoticspindle-associated poly(ADP-ribose). The poly(ADP-ribosyl)ation activityof TANK-1 might be crucial for the accurate formation and maintenance ofspindle bipolarity. Furthermore, PARP activity of TANK-1 has been shownto be required for normal telomere separation before anaphase.Interference with tankyrase PARP activity results in aberrant mitosis,which engenders a transient cell cycle arrest, probably due to spindlecheckpoint activation, followed by cell death. Inhibition of tankyrasesis therefore expected to have a cytotoxic effect on proliferating tumorcells (WO 2008/107478).

PARP inhibitors are described by M. Rouleau et al. in Nature Reviews,Volume 10, 293-301 in clinical cancer studies (Table 2, page 298).

According to a review by Horvath and Szabo (Drug News Perspect 20(3),April 2007, 171-181) most recent studies demonstrated that PARPinhibitors enhance the cancer cell death primarily because theyinterfere with DNA repair on various levels. More recent studies havealso demonstrated that PARP inhibitors inhibit angiogenesis, either byinhibiting growth factor expression, or by inhibiting growthfactor-induced cellular proliferative responses. These findings mightalso have implications on the mode of PARP inhibitors' anticancereffects in vivo.

Also a study by Tentori et al. (Eur. J. Cancer, 2007, 43 (14) 2124-2133)shows that PARP inhibitors abrogate VEGF or placental growthfactor-induced migration and prevent formation of tubule-like networksin cell-based systems, and impair angiogenesis in vivo. The study alsodemonstrates that growth factor-induced angiogenesis is deficient inPARP-1 knock-out mice. The results of the study provide evidence fortargeting PARP for anti-angiogenesis, adding novel therapeuticimplications to the use of PARP inhibitors in cancer treatment.

Defects in conserved signaling pathways are well known to play key rolesin the origins and behavior of essentially all cancers (E. A. Fearon,Cancer Cell, Vol. 16, Issue 5, 2009, 366-368). The Wnt pathway is atarget for anti-cancer therapy. A key feature of the Wnt pathway is theregulated proteolysis (degradation) of β-catenin by the β-catenindestruction complex. Proteins like WTX, APC or Axin are involved in thedegradation process. A proper degradation of β-catenin is important toavoid an inappropriate activation of the Wnt pathway which has beenobserved in many cancers. Tankyrases inhibit activity of Axin and henceinhibit the degradation of β-catenin.

Consequently, tankyrase inhibitors increase degradation of β-catenin. Apaper in the journal Nature not only offers important new insights intoproteins regulating Wnt signaling but also further supports the approachto antagonize ρ-catenin levels and localization via small molecules(Huang et al., 2009; Nature, Vol 461, 614-620). The compound XAV939inhibits growth of DLD-1-cancer cells. They found that XAV9393 blockedWnt-stimulated accumulation of ρ-catenin by increasing the levels of theAXIN1 and AXIN2 proteins. Subsequent work by the authors establishedthat XAV939 regulates AXIN levels via inhibition of tankyrases 1 and 2(TNKS1 and TNKS2), both of which are members of the poly(ADP-ribose)polymerase (PARP) protein family (S. J. Hsiao et al., Biochimie 90,2008, 83-92).

It has been found that the compounds according to the invention andsalts thereof have very valuable pharmacological properties while beingwell tolerated.

The present invention specifically relates to compounds of the formula Iwhich inhibit Tankyrase 1 and 2, to compositions which comprise thesecompounds, and to processes for the use thereof for the treatment ofTANK-induced diseases and complaints.

The compounds of the formula I can furthermore be used for the isolationand investigation of the activity or expression of TANKs. In addition,they are particularly suitable for use in diagnostic methods fordiseases in connection with unregulated or disturbed TANK activity.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be determined by in vitro tests.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow active agents such as anti IgM to induce a cellularresponse such as expression of a surface marker, usually between aboutone hour and one week. In vitro testing can be carried out usingcultivated cells from blood or from a biopsy sample. The amount ofsurface marker expressed is assessed by flow cytometry using specificantibodies recognising the marker.

The dose varies depending on the specific compound used, the specificdisease, the patient status, etc. A therapeutic dose is typicallysufficient considerably to reduce the undesired cell population in thetarget tissue while the viability of the patient is maintained. Thetreatment is generally continued until a considerable reduction hasoccurred, for example an at least about 50% reduction in the cellburden, and may be continued until essentially no more undesired cellsare detected in the body.

PRIOR ART

-   E. Wahlberg et al., Nature Biotechnology (2012), 30(3), 283.-   H. Bregman et al., Journal of Medicinal Chemistry (2013), 56(3),    1341-   Other tankyrase inhibitors are described in WO 2013/012723, WO    2013/010092, WO 2012/076898 and in WO 2013/008217.

WO2004/033427 describes the preparation of 1,4-disubstituted piperidinederivatives and their use as 11-ρHSD1 inhibitors for the treatment ofdiabetes and related diseases:

4-(4-fluorobenzoyl)-N-methyl-N-phenyl-piperidine-1-carboxamide

and

4-(4-fluorobenzoyl)-N-(4-fluorophenyl)-N-methyl-piperidine-1-carboxamide

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I

in which

-   R¹ denotes A or CH₂COOA,-   R², R³ each, independently of one another, denote Ar or Het¹,-   R¹ and R² together with the N atom to which they are attached,    denote a heterocylic ring selected from 2,3-dihydro-indolyl or    3,4-dihydro-quinolyl,-   Het¹ denotes pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of    which may mono-, di- or trisubstituted by Hal, A, OH, CN and/or OA,-   Ar denotes phenyl, which is unsubstituted, or mono-, di- or    trisubstituted by Hal, NO₂, CN, A, OR⁴, S(O)_(m)R⁴, N(R⁴)₂, COA,    COOR⁴, CON(R⁴)₂, SO₂N(R⁴)₂, NR⁴COR⁴, NR⁴SO₂A, NR⁴CON(R⁴)₂ and/or    Het²,-   R⁴ denotes H or A′,-   A denotes unbranched or branched alkyl with 1-8 C-Atoms, wherein one    or two non-adjacent CH- and/or CH₂-groups may be replaced by N- or    O-atoms and wherein 1-7 H-atoms may be replaced by F or Cl,-   A′ denotes unbranched or branched alkyl with 1, 2, 3 or 4 C-Atoms,-   Het² denotes pyrazolyl, which may be substituted by A or    (CH₂)_(n)Het³,-   Het³ denotes pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl,    each of which may substituted by A,-   Hal denotes F, Cl, Br or I,-   m denotes 0, 1 or 2,-   n denotes 1, 2, 3 or 4,    with the proviso, that    4-(4-fluorobenzoyl)-N-methyl-N-phenyl-piperidine-1-carboxamide and    4-(4-fluorobenzoyl)-N-(4-fluorophenyl)-N-methyl-piperidine-1-carboxamide    are excluded,    and pharmaceutically acceptable salts, tautomers and stereoisomers    thereof, including mixtures thereof in all ratios.

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds.

Moreover, the invention relates to pharmaceutically acceptablederivatives of compounds of formula I.

The term solvates of the compounds is taken to mean adductions of inertsolvent molecules onto the compounds which form owing to their mutualattractive force. Solvates are, for example, mono- or dihydrates oralkoxides.

It is understood, that the invention also relates to the solvates of thesalts. The term pharmaceutically acceptable derivatives is taken tomean, for example, the salts of the compounds according to the inventionand also so-called prodrug compounds.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound of formula I that can hydrolyze, oxidize, orotherwise react under biological conditions (in vitro or in vivo) toprovide an active compound, particularly a compound of formula I.Examples of prodrugs include, but are not limited to, derivatives andmetabolites of a compound of formula I that include biohydrolyzablemoieties such as biohydrolyzable amides, biohydrolyzable esters,biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzableureides, and biohydrolyzable phosphate analogues. In certainembodiments, prodrugs of compounds with carboxyl functional groups arethe lower alkyl esters of the carboxylic acid. The carboxylate estersare conveniently formed by esterifying any of the carboxylic acidmoieties present on the molecule. Prodrugs can typically be preparedusing well-known methods, such as those described by Burger's MedicinalChemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001,Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985,Harwood Academic Publishers Gmfh).

The expression “effective amount” denotes the amount of a medicament orof a pharmaceutical active ingredient which causes in a tissue, system,animal or human a biological or medical response which is sought ordesired, for example, by a researcher or physician.

In addition, the expression “therapeutically effective amount” denotesan amount which, compared with a corresponding subject who has notreceived this amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side-effects or also thereduction in the advance of a disease, complaint or disorder.

The expression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The invention also relates to the use of mixtures of the compounds ofthe formula I, for example mixtures of two diastereomers, for example inthe ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The concentrations of the isomeric formswill depend on the environment the compound is found in and may bedifferent depending upon, for example, whether the compound is a solidor is in an organic or aqueous solution.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI and pharmaceutically acceptable salts, solvates, tautomers andstereoisomers thereof, characterised in that

a compound of the formula II

in which R¹ and R² have the meanings indicated in Claim 1,is reactedwith a compound of formula III

in which R³ has the meanings indicated in Claim 1,and with phosgene or triphosgene,and/ora base or acid of the formula I is converted into one of its salts.

Above and below, the radicals R¹, R², R³ have the meanings indicated forthe formula I, unless expressly stated otherwise.

A denotes alkyl, this is unbranched (linear) or branched, and has 2, 3,4, 5, 6, 7 or 8 C atoms. A preferably denotes ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-,2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl,hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, furthermorepreferably, for example, trifluoromethyl. A very particularly preferablydenotes alkyl having 2, 3, 4, 5 or 6 C atoms, preferably ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl,trifluoromethyl, pentafluoroethyl or 1,1,1-trifluoroethyl. Moreover, Adenotes preferably CH₂OCH₃, CH₂CH₂OH or CH₂CH₂OCH₃. A preferably alsodenotes unbranched or branched alkyl with 1-8 C-Atoms, wherein one ortwo non-adjacent CH₂-groups may be replaced by O-atoms.

R¹ preferably denotes methyl, ethyl, 2-hydroxyethyl or CH₂COOEt.

R² preferably denotes Ar.

R³ preferably denotes Ar.

R³ particularly preferably denotes Ar or Het¹.

R⁴ preferably denotes H, methyl, ethyl, propyl or butyl.

Ar denotes preferably o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m-or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- orp-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl,o-, m- or p-aminophenyl, o-, m- or p-(N-methylamino)phenyl, o-, m- orp-(N-methylaminocarbonyl)phenyl, o-, m- or p-methoxyphenyl, o-, m- orp-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- orp-(N,N-dimethylamino)phenyl, o-, m- orp-(N,N-dimethylaminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)phenyl, o-, m-or p-cyanophenyl, o-, m- or p-carboxyphenyl, o-, m- orp-methoxycarbonylphenyl, o-, m- or p-formylphenyl, o-, m- orp-acetylphenyl, o-, m- or p-aminosulfonylphenyl, furthermore preferably2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-,2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-,2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-,2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar furthermore preferably denotes phenyl, which is unsubstituted, ormono- or disubstituted by Hal, CN, A, OA, NHSO₂A and/or Het².

Het¹ preferably denotes pyridyl, which may be monosubstituted by OA.

Throughout the invention, all radicals which occur more than once may beidentical or different, i.e. are independent of one another.

The compounds of the formula I may have one or more chiral centres andcan therefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to Id, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   in Ia Ar denotes phenyl, which is unsubstituted, or mono- or    disubstituted by Hal, CN, A, OA, NHSO₂A and/or Het²;-   in Ib A denotes unbranched or branched alkyl with 1-8 C-Atoms,    wherein one or two non-adjacent CH₂-groups may be replaced by    O-atoms;-   in Ic R¹ denotes A or CH₂COOA,    -   R², R³ denote Ar,    -   R¹ and R² together with the N atom to which they are attached,        denote a heterocylic ring selected from 2,3-dihydro-indolyl or        3,4-dihydro-quinolyl,    -   Ar denotes phenyl, which is unsubstituted, or mono-, di- or        trisubstituted by Hal, CN, A, OA, NHSO₂A and/or Het²,    -   R⁴ denotes H or A′,    -   A denotes unbranched or branched alkyl with 1-8 C-Atoms, wherein        one or two non-adjacent CH₂-groups may be replaced by O-atoms,    -   A′ denotes unbranched or branched alkyl with 1, 2, 3 or 4        C-Atoms,    -   Het² denotes pyrazolyl, which may be substituted by A or        (CH₂)_(n)Het³,    -   Het³ denotes pyrrolidinyl, piperidinyl, morpholinyl or        piperazinyl, each of which may substituted by A,    -   Hal denotes F, Cl, Br or I,    -   m denotes 0, 1 or 2,    -   n denotes 1, 2, 3 or 4;-   in Id R¹ denotes A or CH₂COOA,-   R² denotes Ar,-   R³ denotes Ar or Het¹,-   R¹ and R² together with the N atom to which they are attached,    denote a heterocylic ring selected from 2,3-dihydro-indolyl or    3,4-dihydro-quinolyl,-   Ar denotes phenyl, which is unsubstituted, or mono- or disubstituted    by Hal, CN, A, OA, NHSO₂A and/or Het²,-   R⁴ denotes H or A′,-   A denotes unbranched or branched alkyl with 1-8 C-Atoms, wherein one    or two non-adjacent CH₂-groups may be replaced by O-atoms,-   A′ denotes unbranched or branched alkyl with 1, 2, 3 or 4 C-Atoms,-   Het¹ denotes pyridyl, which may monosubstituted by OA,-   Het² denotes pyrazolyl, which may be substituted by A or    (CH₂)_(n)Het³,-   Het³ denotes pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl,    each of which may substituted by A,-   Hal denotes F, Cl, Br or I,-   m denotes 0, 1 or 2,-   n denotes 1, 2, 3 or 4;    and pharmaceutically acceptable salts, tautomers and stereoisomers    thereof, including mixtures thereof in all ratios.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants known per se which are notmentioned here in greater detail.

The starting compounds of the formula II and III are generally known. Ifthey are novel, however, they can be prepared by methods known per se.

Compounds of the formula I can preferably be obtained by reacting acompound of the formula II with a compound of the formula III and withphosgene or triphosgene.

The reaction is generally carried out in the presence of an acid-bindingagent, preferably an organic base, such as DIPEA, triethylamine,dimethylaniline, pyridine or quinoline.

The addition of an alkali or alkaline earth metal hydroxide, carbonateor bicarbonate or another salt of a weak acid of the alkali or alkalineearth metals, preferably of potassium, sodium, calcium or caesium, mayalso be favourable.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° and140°, normally between −10° and 60°, in particular between about 0° andabout 30°.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro com-pounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Particular preference is given to acetonitrile, 1,2-dichloroethane,dichloromethane and/or DMF.

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminium saltsof the compounds of the formula I are likewise included. In the case ofcertain compounds of the formula I, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds of the formula I include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, formate,galacterate (from mucic acid), galacturonate, glucoheptanoate,gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate,heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate,lactate, lactobionate, malate, maleate, malonate, mandelate,metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

Particular preference is given to hydrochloride, dihydrochloride,hydrobromide, maleate, mesylate, phosphate, sulfate and succinate.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

Isotopes

There is furthermore intended that a compound of the formula I includesisotope-labelled forms thereof. An isotope-labelled form of a compoundof the formula I is identical to this compound apart from the fact thatone or more atoms of the compound have been replaced by an atom or atomshaving an atomic mass or mass number which differs from the atomic massor mass number of the atom which usually occurs naturally. Exam-pies ofisotopes which are readily commercially available and which can beincorporated into a compound of the formula I by well-known methodsinclude isotopes of hydrogen, carbon, nitrogen, oxygen, phos-phorus,fluo-rine and chlorine, for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O,³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. A compound of the formula I,a prodrug, thereof or a pharmaceutically acceptable salt of either whichcontains one or more of the above-mentioned isotopes and/or otheriso-topes of other atoms is intended to be part of the presentinvention. An isotope-labelled compound of the formula I can be used ina number of beneficial ways. For example, an isotope-labelled compoundof the formula I into which, for example, a radioisotope, such as ³H or¹⁴C, has been incorporated is suitable for medicament and/or substratetissue distribution assays. These radioisotopes, i.e. tritium (³H) andcarbon-14 (¹⁴C), are particularly preferred owing to simple preparationand excellent detectability. Incor-po-ra-tion of heavier isotopes, forexample deuterium (²H), into a compound of the formula I has therapeuticadvantages owing to the higher metabolic stability of thisisotope-labelled compound. Higher metabolic stability translatesdirectly into an increased in vivo half-life or lower dosages, whichunder most circumstances would represent a preferred embodi-ment of thepresent invention. An isotope-labelled compound of the formula I canusually be prepared by carrying out the procedures dis-closed in thesynthesis schemes and the related description, in the example part andin the preparation part in the present text, replacing anon-isotope-labelled reactant by a readily available isotope-labelledreactant.

Deuterium (²H) can also be incorporated into a compound of the formula Ifor the purpose in order to manipulate the oxidative metabolism of thecompound by way of the primary kinetic isotope effect. The primarykinetic isotope effect is a change of the rate for a chemical reactionthat results from exchange of isotopic nuclei, which in turn is causedby the change in ground state energies necessary for covalent bondformation after this isotopic exchange. Exchange of a heavier isotopeusually results in a lowering of the ground state energy for a chemicalbond and thus cause a reduction in the rate in rate-limiting bondbreakage. If the bond breakage occurs in or in the vicinity of asaddle-point region along the coordinate of a multi-product reaction,the product distribution ratios can be altered substantially. Forexplanation: if deuterium is bonded to a carbon atom at anon-exchangeable position, rate differences of k_(M)/k_(D)=2-7 aretypical. If this rate difference is successfully applied to a com-poundof the formula I that is susceptible to oxidation, the profile of thiscompound in vivo can be drastically modified and result in improvedpharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilledin the art attempts to optimise pharmacokinetic parameters whileretaining desirable in vitro properties. It is reasonable to assume thatmany com-pounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In vitro liver microsomal assays currentlyavailable provide valuable information on the course of oxidativemetabolism of this type, which in turn permits the rational design ofdeuterated compounds of the formula I with improved stability throughresistance to such oxidative meta-bolism. Significant improvements inthe pharmacokinetic profiles of compounds of the formula I are therebyobtained, and can be expressed quantitatively in terms of increases inthe in vivo half-life (t/2), concen-tra-tion at maximum therapeuticeffect (C_(max)), area under the dose response curve (AUC), and F; andin terms of reduced clearance, dose and materi-als costs.

The following is intended to illustrate the above: a compound of theformula I which has multiple potential sites of attack for oxidativemetabolism, for example benzylic hydrogen atoms and hydrogen atomsbonded to a nitrogen atom, is prepared as a series of analogues in whichvarious combinations of hydrogen atoms are replaced by deuterium atoms,so that some, most or all of these hydrogen atoms have been replaced bydeuterium atoms. Half-life determinations enable favourable and accuratedetermination of the extent of the extent to which the improve-ment inresistance to oxidative metabolism has improved. In this way, it isdeter-mined that the half-life of the parent compound can be extended byup to 100% as the result of deuterium-hydrogen exchange of this type.

Deuterium-hydrogen exchange in a compound of the formula I can also beused to achieve a favourable modification of the metabolite spectrum ofthe starting compound in order to diminish or eliminate undesired toxicmetabolites. For example, if a toxic metabolite arises through oxidativecarbon-hydrogen (C—H) bond cleavage, it can reasonably be assumed thatthe deuterated analogue will greatly diminish or eliminate production ofthe unwanted metabolite, even if the particular oxidation is not arate-determining step. Further information on the state of the art withrespect to deuterium-hydrogen exchange may be found, for example inHanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J.Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985,Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al.Carcinogenesis 16(4), 683-688, 1993.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically acceptablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and optionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the condition treated,the method of administration and the age, weight and condition of thepatient, or pharmaceutical formulations can be administered in the formof dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbant, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tabletting machine, giving lumps of non-uniform shape, whichare broken up to form granules. The granules can be lubricated byaddition of stearic acid, a stearate salt, talc or mineral oil in orderto prevent sticking to the tablet casting moulds. The lubricated mixtureis then pressed to give tablets. The compounds according to theinvention can also be combined with a free-flowing inert excipient andthen pressed directly to give tablets without carrying out thegranulation or dry-pressing steps. A transparent or opaque protectivelayer consisting of a shellac sealing layer, a layer of sugar or polymermaterial and a gloss layer of wax may be present. Dyes can be added tothese coatings in order to be able to differentiate between differentdosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa prespecified amount of the compound. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds of the formula I and pharmaceutically salts, tautomers andstereoisomers thereof can also be administered in the form of liposomedelivery systems, such as, for example, small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from various phospholipids, such as, for example, cholesterol,stearylamine or phosphatidylcholines.

The compounds of the formula I and the salts, tautomers andstereoisomers thereof can also be delivered using monoclonal antibodiesas individual carriers to which the compound molecules are coupled. Thecompounds can also be coupled to soluble polymers as targeted medicamentcarriers. Such polymers may encompass polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamidophenol,polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine,substituted by palmitoyl radicals. The compounds may furthermore becoupled to a class of biodegradable polymers which are suitable forachieving controlled release of a medicament, for example polylacticacid, poly-epsilon-caprolactone, polyhydroxybutyric acid,polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylatesand crosslinked or amphipathic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base.

Alternatively, the active ingredient can be formulated to give a creamwith an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the formula Idepends on a number of factors, including, for example, the age andweight of the animal, the precise condition that requires treatment, andits severity, the nature of the formulation and the method ofadministration, and is ultimately determined by the treating doctor orvet. However, an effective amount of a compound according to theinvention is generally in the range from 0.1 to 100 mg/kg of body weightof the recipient (mammal) per day and particularly typically in therange from 1 to 10 mg/kg of body weight per day. Thus, the actual amountper day for an adult mammal weighing 70 kg is usually between 70 and 700mg, where this amount can be administered as a single dose per day orusually in a series of part-doses (such as, for example, two, three,four, five or six) per day, so that the total daily dose is the same. Aneffective amount of a salt or solvate or of a physiologically functionalderivative thereof can be determined as the fraction of the effectiveamount of the compound according to the invention per se. It can beassumed that similar doses are suitable for the treatment of otherconditions mentioned above.

A combined treatment of this type can be achieved with the aid ofsimultaneous, consecutive or separate dispensing of the individualcomponents of the treatment. Combination products of this type employthe compounds according to the invention.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically acceptable salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios, and at least one further medicament active ingredient.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula I and/or    pharmaceutically acceptable salts, tautomers and stereoisomers    thereof, including mixtures thereof in all ratios, and-   (b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound of theformula I and/or pharmaceutically acceptable salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios,

and an effective amount of a further medicament active ingredient indissolved or lyophilised form.

“Treating” as used herein, means an alleviation, in whole or in part, ofsymptoms associated with a disorder or disease, or slowing, or haltingof further progression or worsening of those symptoms, or prevention orprophylaxis of the disease or disorder in a subject at risk fordeveloping the disease or disorder.

The term “effective amount” in connection with a compound of formula (I)can mean an amount capable of alleviating, in whole or in part, symptomsassociated with a disorder or disease, or slowing or halting furtherprogression or worsening of those symptoms, or preventing or providingprophylaxis for the disease or disorder in a subject having or at riskfor developing a disease disclosed herein, such as inflammatoryconditions, immunological conditions, cancer or metabolic conditions.

In one embodiment an effective amount of a compound of formula (I) is anamount that inhibits a tankyrase in a cell, such as, for example, invitro or in vivo. In some embodiments, the effective amount of thecompound of formula (I) inhibits tankyrase in a cell by 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90% or 99%, compared to the activity oftankyrase in an untreated cell. The effective amount of the compound offormula (I), for example in a pharmaceutical composition, may be at alevel that will exercise the desired effect; for example, about 0.005mg/kg of a subject's body weight to about 10 mg/kg of a subject's bodyweight in unit dosage for both oral and parenteral administration.

Use

The present compounds are suitable as pharmaceutical active ingredientsfor mammals, especially for humans, in the treatment of cancer, multiplesclerosis, cardiovascular diseases, central nervous system injury anddifferent forms of inflammation.

The present invention encompasses the use of the compounds of theformula I and/or pharmaceutically acceptable salts, tautomers andstereoisomers thereof for the preparation of a medicament for thetreatment or prevention of cancer, multiple sclerosis, cardiovasculardiseases, central nervous system injury and different forms ofinflammation.

Examples of inflammatory diseases include rheumatoid arthritis,psoriasis, contact dermatitis, delayed hypersensitivity reaction and thelike.

Also encompassed is the use of the compounds of the formula I and/orpharmaceutically acceptable salts, tautomers and stereoisomers thereoffor the preparation of a medicament for the treatment or prevention of atankyrase-induced disease or a tankyrase-induced condition in a mammal,in which to this method a therapeutically effective amount of a compoundaccording to the invention is administered to a sick mammal in need ofsuch treatment. The therapeutic amount varies according to the specificdisease and can be determined by the person skilled in the art withoutundue effort.

The expression “tankyrase-induced diseases or conditions” refers topathological conditions that depend on the activity of one or moretankyrases. Diseases associated with tankyrase activity include cancer,multiple sclerosis, cardiovascular diseases, central nervous systeminjury and different forms of inflammation.

The present invention specifically relates to compounds of the formula Iand pharmaceutically acceptable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios,

for the use for the treatment of diseases in which the inhibition,regulation and/or modulation inhibition of tankyrase plays a role.

The present invention specifically relates to compounds of the formula Iand pharmaceutically acceptable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios, for the use for theinhibition of tankyrase.

The present invention specifically relates to compounds of the formula Iand pharmaceutically acceptable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios, for the use for thetreatment of cancer, multiple sclerosis, cardiovascular diseases,central nervous system injury and different forms of inflammation.

The present invention specifically relates to methods for treating orpreventing cancer, multiple sclerosis, cardiovascular diseases, centralnervous system injury and different forms of inflammation, comprisingadministering to a subject in need thereof an effective amount of acompound of formula I or a pharmaceutically acceptable salt, tautomer,stereoisomer or solvate thereof.

Representative cancers that compounds of formula I are useful fortreating or preventing include, but are not limited to, cancer of thehead, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx,chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder,uterine, cervix, breast, ovaries, testicles or other reproductiveorgans, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas,brain, central nervous system, solid tumors and blood-borne tumors.

Representative cardiovascular diseases that compounds of formula I areuseful for treating or preventing include, but are not limited to,restenosis, atherosclerosis and its consequences such as stroke,myocardial infarction, ischemic damage to the heart, lung, gut, kidney,liver, pancreas, spleen or brain.

The present invention relates to a method of treating a proliferative,autoimmune, anti inflammatory or infectious disease disorder thatcomprises administering to a subject in need thereof a therapeuticallyeffective amount of a compound of formula I.

Preferably, the present invention relates to a method wherein thedisease is a cancer.

Particularly preferable, the present invention relates to a methodwherein the disease is a cancer, wherein administration is simultaneous,sequential or in alternation with administration of at least one otheractive drug agent.

The disclosed compounds of the formula I can be administered incombination with other known therapeutic agents, including anticanceragents. As used here, the term “anticancer agent” relates to any agentwhich is administered to a patient with cancer for the purposes oftreating the cancer.

The anti-cancer treatment defined above may be applied as a monotherapyor may involve, in addition to the herein disclosed compounds of formulaI, conventional surgery or radiotherapy or medicinal therapy. Suchmedicinal therapy, e.g. a chemotherapy or a targeted therapy, mayinclude one or more, but preferably one, of the following anti-tumoragents:

Alkylating Agents

such as altretamine, bendamustine, busulfan, carmustine, chlorambucil,chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan,tosilate, lomustine, melphalan, mitobronitol, mitolactol, nimustine,ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine,carboquone; apaziquone, fotemustine, glufosfamide, palifosfamide,pipobroman, trofosfamide, uramustine, TH-302⁴, VAL-083⁴;Platinum Compoundssuch as carboplatin, cisplatin, eptaplatin, miriplatine hydrate,oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin;lobaplatin, nedaplatin, picoplatin, satraplatin;DNA Altering Agentssuch as amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine,trabectedin, clofarabine;amsacrine, brostallicin, pixantrone, laromustine^(1,3);Topoisomerase Inhibitorssuch as etoposide, irinotecan, razoxane, sobuzoxane, teniposide,topotecan; amonafide, belotecan, elliptinium acetate, voreloxin;Microtubule Modifierssuch as cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel,vinblastine, vincristine, vinorelbine, vindesine, vinflunine;fosbretabulin, tesetaxel;Antimetabolitessuch as asparaginase³, azacitidine, calcium levofolinate, capecitabine,cladribine, cytarabine, enocitabine, floxuridine, fludarabine,fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine,pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur;doxifluridine, elacytarabine, raltitrexed, sapacitabine, tegafur^(2,3),trimetrexate;Anticancer Antibioticssuch as bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin,levamisole, miltefosine, mitomycin C, romidepsin, streptozocin,valrubicin, zinostatin, zorubicin, daunurobicin, plicamycin;aclarubicin, peplomycin, pirarubicin;Hormones/Antagonistssuch as abarelix, abiraterone, bicalutamide, buserelin, calusterone,chlorotrianisene, degarelix, dexamethasone, estradiol, fluocortolonefluoxymesterone, flutamide, fulvestrant, goserelin, histrelin,leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide,octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa,toremifene, trilostane, triptorelin, diethylstilbestrol;acolbifene, danazol, deslorelin, epitiostanol, orteronel,enzalutamide^(1,3);Aromatase Inhibitorssuch as aminoglutethimide, anastrozole, exemestane, fadrozole,letrozole, testolactone;formestane;Small Molecule Kinase Inhibitorssuch as crizotinib, dasatinib, erlotinib, imatinib, lapatinib,nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib,vandetanib, vemurafenib, bosutinib, gefitinib, axitinib;afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib,enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib,midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib,radotinib, rigosertib, tipifarnib, tivantinib, tivozanib, trametinib,pimasertib, brivanib alaninate, cediranib, apatinib⁴, cabozantinibS-malate^(1,3), ibrutinib^(1,3), icotinib⁴, buparlisib², cipatinib⁴,cobimetinib^(1,3), idelalisib^(1,3), fedratinib¹, XL-647⁴;Photosensitizerssuch as methoxsalen³;porfimer sodium, talaporfin, temoporfin;Antibodiessuch as alemtuzumab, besilesomab, brentuximab vedotin, cetuximab,denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab,trastuzumab, bevacizumab, pertuzumab^(2,3);catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab,necitumumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab,ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab,zanolimumab, matuzumab, dalotuzumab^(1,2,3), onartuzumab^(1,3),racotumomab¹, tabalumab^(1,3), EMD-525797⁴, nivolumab^(1,3);Cytokinessuch as aldesleukin, interferon alfa², interferon alfa2a³, interferonalfa2b^(2,3); celmoleukin, tasonermin, teceleukin, oprelvekin^(1,3),recombinant interferon beta-1a⁴;Drug Conjugatessuch as denileukin diftitox, ibritumomab tiuxetan, iobenguane I123,prednimustine, trastuzumab emtansine, estramustine, gemtuzumab,ozogamicin, aflibercept;cintredekin besudotox, edotreotide, inotuzumab ozogamicin, naptumomabestafenatox, oportuzumab monatox, technetium (99mTc) arcitumomab^(1,3),vintafolide^(1,3);Vaccinessuch as sipuleucel³; vitespen³, emepepimut-S³, oncoVAX⁴, rindopepimut³,troVax⁴, MGN-1601⁴, MGN-1703⁴;Miscellaneousalitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid,imiquimod, lenalidomide, lentinan, metirosine, mifamurtide, pamidronicacid, pegaspargase, pentostatin, sipuleucel³, sizofiran, tamibarotene,temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid,vorinostat; celecoxib, cilengitide, entinostat, etanidazole, ganetespib,idronoxil, iniparib, ixazomib, lonidamine, nimorazole, panobinostat,peretinoin, plitidepsin, pomalidomide, procodazol, ridaforolimus,tasquinimod, telotristat, thymalfasin, tirapazamine, tosedostat,trabedersen, ubenimex, valspodar, gendicine⁴, picibanil⁴, reolysin⁴,retaspimycin hydrochloride^(1,3), trebananib^(2,3), virulizin⁴,carfilzomib^(1,3), endostatin⁴, immucothel⁴, belinostat³, MGN-1703⁴; ¹Prop. INN (Proposed International Nonproprietary Name)² Rec. INN(Recommended International Nonproprietary Names)³ USAN (United StatesAdopted Name)⁴ no INN.

The following abbreviations refer respectively to the definitions below:

aq (aqueous), h (hour), g (gram), L (liter), mg (milligram), MHz(Megahertz), min. (minute), mm (millimeter), mmol (millimole), mM(millimolar), m.p. (melting point), eq (equivalent), mL (milliliter), L(microliter), ACN (acetonitrile), AcOH (acetic acid), CDCl₃ (deuteratedchloroform), CD₃OD (deuterated methanol), CH₃CN (acetonitrile), c-hex(cyclohexane), DCC (dicyclohexyl carbodiimide), DCM (dichloromethane),DIC (diisopropyl carbodiimide), DIEA (diisopropylethyl-amine), DMF(dimethylformamide), DMSO (dimethylsulfoxide), DMSO-d₆ (deuterateddimethylsulfoxide), EDC(1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide), ESI (Electro-sprayionization), EtOAc (ethyl acetate), Et₂O (diethyl ether), EtOH(ethanol), HATU(dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethylammoniumhexafluorophosphate), HPLC (High Performance Liquid Chromatography),i-PrOH (2-propanol), K₂CO₃ (potassium carbonate), LC (LiquidChromatography), MeOH (methanol), MgSO₄ (magnesium sulfate), MS (massspectrometry), MTBE (Methyl tert-butyl ether), NaHCO₃ (sodiumbicarbonate), NaBH₄ (sodium borohydride), NMM (N-methyl morpholine), NMR(Nuclear Magnetic Resonance), PyBOP(benzotriazole-1-yl-oxy-trispyrrolidino-phosphoniumhexafluorophosphate), RT (room temperature), Rt (retention time), SPE(solid phase extraction), TBTU(2-(1-H-benzotriazole-1-yl)-1,1,3,3-tetramethyluromium tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid), THF(tetrahydrofuran), TLC (Thin Layer Chromatography), UV (Ultraviolet).Description of the In Vitro AssaysAbbreviations:GST=Glutathione-S-transferaseFRET=Fluorescence resonance energy transferHTRF®=(homogenous time resolved fluorescence)HEPES=4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid bufferDTT=DithiothreitolBSA=bovine serum albuminCHAPS=detergent;CHAPS=3[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate

Streptavidin-XLent® is a high grade streptavidin-XL665 conjugate forwhich the coupling conditions have been optimized to yield a conjugatewith enhanced performances for some assays, particularly those requiringhigh sensitivity.

Biochemical activity testing of Tankyrase 1 and 2: Autoparsylation assay

The autoparsylation assay is run in two steps: the enzymatic reaction inwhich GST-tagged Tankyrase-1, resp Tankyrase-2 transferred biotinylatedADP-ribose to itself from biotinylated NAD as co-substrate and thedetection reaction where a time resolved FRET between cryptate labelledanti-GST bound to the GST tag of the enzyme and Xlent®labelled-streptavidin bound the biotin-parsylation residue is analysed.The autoparsylation activity was detectable directly via the increase inHTRF signal.

The autoparsylation assay is performed as 384-well HTRF® (Cisbio,Codolet, France) assay format in Greiner low volume nb 384-wellmicrotiter plates and is used for high throughput screen. 250 nMGST-tagged Tankyrase-1 (1023-1327 aa), respectively about 250 nMGST-tagged Tankyrase-2 (873-1166 aa) and 5 μM bio-NAD (Biolog, Lifescience Inst., Bremen, Germany) as co-substrate are incubated in a totalvolume of 5 μl (50 mM HEPES, 4 mM Mg-chloride, 0.05% Pluronic F-68, 1.4mM DTT, 0.5% DMSO, pH 7.7) in the absence or presence of the testcompound (10 dilution concentrations) for 90 min at 30° C. The reactionis stopped by the addition of 1 μl 50 mM EDTA solution. 2 μl of thedetection solution (1.6 μM SA-Xlent® (Cisbio, Codolet, France), 7.4 nMAnti-GST-K® (Eu-labelled anti-GST, Cisbio, Codolet, France) in 50 mMHEPES, 800 mM KF, 0.1% BSA, 20 mM EDTA, 0.1% CHAPS, pH 7.0) are added.After 1 h incubation at room temperature the HTRF is measured with anEnvision multimode reader (Perkin Elmer LAS Germany GmbH) at excitationwavelength 340 nm (laser mode) and emission wavelengths 615 nm and 665nm. The ratio of the emission signals is determined. The full value usedis the inhibitor-free reaction. The pharmacological zero value used isXAV-939 (Tocris) in a final concentration of 5 μM. The inhibitory values(IC50) are determined using either the program Symyx Assay Explorer® orCondosseo® from GeneData.

Measurement of Cellular Inhibition of Tankyrase

Since Tankyrases have been described to modulate cellular level of Axin2(Huang et al., 2009; Nature) the increase of Axin2 level is used asread-out for determination of cellular inhibition of Tankyrases in aLuminex based assay.

Cells of the colon carcinoma cell line DLD1 are plated in 96 well plateswith 1.5×10⁴ cells per well. Next day, cells are treated with a serialdilution of test compound in seven steps as triplicates with a finalDMSO concentration of 0.3%. After 24 hours, cells are lysed in lysisbuffer (20 mM Tris/HCl pH 8.0, 150 mM NaCl, 1% NP40, 10% Glycerol) andlysates are cleared by centrifugation through a 96 well filter plate(0.65 μm). Axin2 protein is isolated from cell lysates by incubationwith a monoclonal anti-Axin2 antibody (R&D Systems #MAB6078) that isbound to fluorescent carboxybeads. Then, bound Axin2 is specificallydetected with a polyclonal anti-Axin2 antibody (Cell Signaling #2151)and an appropriate PE-fluorescent secondary antibody. The amount ofisolated Axin2 protein is determined in a Luminex²⁰⁰ machine (LuminexCorporation) according to the manufacturer's instruction by counting 100events per well. Inhibition of Tankyrase by test compounds results inhigher levels of Axin2 which directly correlates with an increase ofdetectable fluorescence. As controls cells are treated with solventalone (neutral control) and with a Tankyrase reference inhibitor IWR-2(3E-06 M) which refers as control for maximum increase of Axin2. Foranalysis, the obtained data are normalized against the untreated solventcontrol and fitted for determination of the EC₅₀ values using the AssayExplorer software (Accelrys).

Description of the PARP1 Assay

Biochemical Activity Testing of PARP-1: Autoparsylation Assay

The autoparsylation assay is run in two steps: the enzymatic reaction inwhich His-tagged Parp-1 transfers biotinylated ADP-ribose/ADP-ribose toitself from biotinylated NAD/NAD as co-substrate and the detectionreaction where a time resolved FRET between cryptate labelled anti-Hisantibody bound to the His tag of the enzyme and Xlent®labelled-streptavidin bound the biotin-parsylation residue is analysed.The autoparsylation activity is detectable directly via the increase inHTRF signal.

The autoparsylation assay is performed as 384-well HTRF® (Cisbio,Codolet, France) assay format in Greiner low volume nb 384-wellmicrotiter plates. 35 nM His-tagged Parp-1 (human, recombinant, EnzoLife Sciences GmbH, Lörrach, Germany) and a mixture of 125 nM bio-NAD(Biolog, Life science Inst., Bremen, Germany) and 800 nM NAD asco-substrate are incubated in a total volume of 6 μl (100 mM Tris/HCl, 4mM Mg-chloride, 0.01% IGEPAL® CA630, 1 mM DTT, 0.5% DMSO, pH 8, 13 ng/μlactivated DNA (BPS Bioscience, San Diego, US)) in the absence orpresence of the test compound (10 dilution concentrations) for 150 minat 23° C. The reaction is stopped by the addition of 4 μl of theStop/detection solution (70 nM SA-Xlent® (Cisbio, Codolet, France), 2.5nM Anti-His-K® (Eu-labelled anti-His, Cisbio, Codolet, France) in 50 mMHEPES, 400 mM KF, 0.1% BSA, 20 mM EDTA, pH 7.0). After 1 h incubation atroom temperature the HTRF iss measured with an Envision multimode reader(Perkin Elmer LAS Germany GmbH) at excitation wavelength 340 nm (lasermode) and emission wavelengths 615 nm and 665 nm. The ratio of theemission signals is determined. The full value used is theinhibitor-free reaction. The pharmacological zero value used is Olaparib(LClabs, Woburn, US) in a final concentration of 1 μM. The inhibitoryvalues (IC50) are determined using either the program Symyx AssayExplorer® or Condosseo® from GeneData.

Description of the TNKS1 and TNKS2 ELISA Assay

Biochemical Activity Testing of TNKS 1 and 2: Activity ELISA(Autoparsylation Assay)

For analysis of autoparsylation activity of TNKS 1 and 2 an activityELISA iss performed: In the first step GST tagged TNKS is captured on aGlutathione coated plate. Then the activity assay with biotinylated NADis performed in the absence/presence of the compounds. During theenzymatic reaction GST tagged TNKS transfers biotinylated ADP-ribose toitself from biotinylated NAD as co-substrate. For the detectionstreptavidin-HRP conjugate is added that binds to the biotinylated TNKSand is thereby captured to the plates. The amount of biotinylated resp.autoparsylated TNKS is detected with a luminescence substrate for HRP.The level of the luminescence signal correlates directly with the amountof autoparsylated TNKS and therefore with activity of TNKS.

The activity ELISA is performed in 384 well Glutathione coatedmicrotiter plates (Express capture Glutathione coated plate, Biocat,Heidelberg, Germany). The plates are pre-equilibrated with PBS. Then theplates are incubated with 50 μl 20 ng/well GST-tagged Tnks-1 (1023-1327aa, prepared in-house), respectively GST-tagged Tnks-2 (873-1166 aa,prepared in-house) in assay buffer (50 mM HEPES, 4 mM Mg-chloride, 0.05%Pluronic F-68, 2 mM DTT, pH 7.7) overnight at 4° C. The plates arewashed 3 times with PBS-Tween-20. The wells are blocked by incubation atroom temperature for 20 minutes with 50 μl blocking buffer (PBS, 0.05%Tween-20, 0.5% BSA). Afterwards the plates are washed 3 times withPBS-Tween-20. The enzymatic reaction is performed in 50 μl reactionsolution (50 mM HEPES, 4 mM Mg-chloride, 0.05% Pluronic F-68, 1.4 mMDTT, 0.5% DMSO, pH 7.7) with 10 μM bio-NAD (Biolog, Life science Inst.,Bremen, Germany) as co-substrate in the absence or presence of the testcompound (10 dilution concentrations) for 1 hour at 30° C. The reactionis stopped by 3 times washing with PBS-Tween20. For the detection 50 μlof 20 ng/μl Streptavidin, HRP conjugate (MoBiTec, Göttingen, Germany) inPBS/0.05% Tween-20/0.01% BSA are added and the plates are incubated for30 minutes at room temperature. After three times washing withPBS-Tween-20 50 μl of SuperSignal ELISA Femto Maximum sensitivitysubstrate solution (ThermoFisherScientific (Pierce), Bonn, Germany) areadded. Following a 1 minute incubation at room temperature luminescencesignals are measured with an Envision multimode reader (Perkin Elmer LASGermany GmbH) at 700 nm. The full value used is the inhibitor-freereaction. The pharmacological zero value used is XAV-939 (Tocris) in afinal concentration of 5 μM. The inhibitory values (IC50) are determinedusing either the program Symyx Assay Explorer® or Condosseo® fromGeneData.

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: water is added if necessary, thepH is adjusted, if necessary, to values between 2 and 10, depending onthe constitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate and evaporated, and the residue is purifiedby chromatography on silica gel and/or by crystallisation. Rf values onsilica gel; eluent: ethyl acetate/methanol 9:1.

¹H NMR was recorded on Bruker 400 MHz spectrometer, using residualsignal of deuterated solvent as internal reference. Chemical shifts (δ)are reported in ppm relative to the residual solvent signal (δ=2.49 ppmfor ¹H NMR in DMSO-d₆). ¹H NMR data are reported as follows: chemicalshift (multiplicity, coupling constants, and number of hydrogens).Multiplicity is abbreviated as follows: s (singlet), d (doublet), t(triplet), q (quartet), m (multiplet), br (broad).

LCMS-Analysis:

Method A:

Solvent A: water+0.1% TFA; Solvent B: ACN+0.1% TFA; Flow: 2 ml/min;Gradient: 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10min 5% B.

Column: XBridge C8, 3.5 μm, 4.6×50 mm;

Method B:

Solvent A: 10 mM NH₄HCO₃, Solvent B: ACN; Flow Rate: 1.0 ml/min

Column: XBridge C8, 3.5 μm, 4.6×50 mm;

HPLC:

Method A:

A-0.1% TFA in H₂O, B-0.1% TFA in ACN: Flow—2.0 mL/min. Column: XBridgeC8 (50×4.6 mm, 3.5 μm).

EXAMPLES phenyl(piperidin-4-yl)methanone

1-acetyl piperidine-4-carboxylic acid (3.0 g, 0.018 mol) was added tothionyl chloride (10 mL, 0.143 mol) in small portions and stirred for 4h at room temperature. The reaction was concentrated under vacuum andcoevaporated with toluene (2×200 mL). The residue was dissolved(sparingly soluble) in 1,2-dichloroethane and added to the stirredsuspension of anhydrous aluminum chloride in benzene (20 mL). Theresulting mixture was refluxed for 2 h, poured into crushed ice andextracted with chloroform (2×200 mL). The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and evaporated to get thebrown gum. The obtained gum was refluxed for 6 h with 6 N hydrochloricacid (60 mL). The reaction was cooled to room temperature and washedwith diethyl ether (100 mL). The aqueous part was rendered basic with10% sodium hydroxide and extracted with diethyl ether (2×100 mL). Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and evaporated to dryness. The residue was purified by columnchromatography using silica gel (60-120) and petrol ether/ethyl acetateas gradient elution to afford the title compound; yield: 1.5 g (45%);LCMS (Method B): 190.3 (M+H), Rt: 2.01 min, purity: 85.3%;

¹H NMR (400 MHz, DMSO-d₆): δ 7.45-7.34 (m, 5H), 3.13 (s, 1H), 2.83 (s,1H), 2.50-2.48 (m, 2H), 1.80-1.70 (m, 1H), 1.30-1.25 (m, 3H), 1.14-1.19(m, 1H).

Example 1 4-benzoyl-piperidine-1-carboxylic acid methyl-m-tolyl-amide(“A1”)

To a suspension of phenyl(piperidin-4-yl)methanone (0.15 g, 0.79 mmol)in DCM (10 mL) was added diisopropylethylamine (0.30 g, 2.37 mmol)followed by triphosgene (0.23 g, 0.79 mmol) in drops at 0° C. Afterbeing stirred for 30 min, the reaction was cooled to 0° C. andmethyl-m-tolyl-amine (0.093 g, 0.87 mmol) was added. The reactionmixture stirred for 16 h at room temperature. The reaction mixture wasdiluted with DCM (20 mL), washed with 10% sodium bicarbonate (50 mL),1.5 N HCl (50 mL), water (50 mL) and brine (50 mL). The organic layerwas dried over anhydrous Na₂SO₄ and evaporated to dryness. The residuewas purified by column chromatography using silica gel (60-120) andpetrol ether/ethyl acetate as gradient elution to afford the titlecompound; yield: 58 mg (26%); LCMS (Method A): 337.2 (M+H), Rt. 4.93min, purity 99.8% (254 nm); HPLC (Method A): Rt. 4.84 min, purity 99.8%(254 nm);

¹H NMR (400 MHz, DMSO-d₆): δ 7.94 (t, J=8.52 Hz, 2H), 7.61 (t, J=14.68Hz, 1H), 7.50 (t, J=15.32 Hz, 2H), 7.22 (t, J=15.48 Hz, 1H), 6.93-6.89(m, 3H), 3.74-3.71 (m, 2H), 3.55-3.49 (m, 1H), 3.06 (s, 3H), 2.79-2.73(m, 2H), 2.28 (s, 3H), 1.61-1.58 (m, 2H), 1.33-1.24 (m, 2H).

Example 2 4-benzoyl-piperidine-1-carboxylic acid methyl-p-tolyl-amide(“A2”)

The compound is prepared analogously to example 1.

Yield: 79 mg (35%); LCMS (Method A): 337.3 (M+H), Rt. 5.57 min, purity:98.2% (254 nm); HPLC (Method A): Rt. 4.86 min, purity 97.8% (254 nm);

¹H NMR (400 MHz, DMSO-d₆): δ 7.92 (d, J=8.52 Hz, 2H), 7.63-7.61 (m, 1H),7.52-7.48 (m, 2H), 7.15 (d, J=8.24 Hz, 2H), 6.99 (t, J=1.96 Hz, 2H),3.70 (d, J=13.00 Hz, 2H), 3.53-3.48 (m, 1H), 3.04 (s, 3H), 2.76-2.70 (m,2H), 2.26 (s, 3H), 1.60 (d, J=11.00 Hz, 2H), 1.32-1.22 (m, 2H).

Example 3 4-benzoyl-piperidine-1-carboxylic acid(3-methoxy-phenyl)-methyl-amide (“A3”)

The compound is prepared analogously to example 1.

Yield: 56 mg (29%); LCMS (Method A): 367.0 (M+H), Rt. 4.73 min, purity96% (254 nm); HPLC (Method A): Rt. 4.57 min, purity 98.5% (254 nm);

¹H NMR (400 MHz, DMSO-d₆): δ 7.96-7.94 (m, 2H), 7.62-7.57 (m, 1H),7.51-7.47 (m, 2H), 7.29 (t, J=16.16 Hz, 1H), 6.76-6.71 (m, 3H), 3.88 (d,J=13.48 Hz, 2H), 3.81 (s, 3H), 3.56-3.49 (m, 1H), 3.19 (s, 3H), 2.85 (t,J=18.16 Hz, 2H), 1.70-1.68 (m, 2H), 1.52-1.48 (m, 2H).

Example 4 4-benzoyl-piperidine-1-carboxylic acid(4-methoxy-phenyl)-methyl-amide (“A4”)

The compound is prepared analogously to example 1.

Yield: 28 mg (12%); LCMS (Method A): 353.2 (M+H), Rt. 4.47 min, purity98.9% (254 nm); HPLC (Method A): Rt. 4.45 min, 99% (254 nm);

¹H NMR (400 MHz, DMSO-d₆): δ 7.93 (d, J=8.48 Hz, 2H), 7.61 (t, J=14.72Hz, 1H), 7.50 (t, J=15.28 Hz, 2H), 7.07 (dd, J=8.88, Hz, 2H), 6.92 (dd,J=12.40 Hz, 2H), 3.73-3.69 (m, 5H), 3.52-3.45 (m, 1H), 3.01 (s, 3H),2.73 (t, J=14.16 Hz, 2H), 1.58 (d, J=11.08 Hz, 2H), 1.30-1.20 (m, 2H).

Example 5 4-(4-methyl-benzoyl)-piperidine-1-carboxylic acid(4-methoxy-phenyl)-methylamide (“A5”)

The compound is prepared analogously to example 1.

Yield: 132 mg (29%); LCMS (Method A): 367.3 (M+H), Rt. 4.80 min, purity99.9% (254 nm); HPLC (Method A): Rt. 4.74 min, 99.8% (254 nm);

¹H NMR (400 MHz, CDCl₃): δ 7.79 (d, J=8.24 Hz, 2H), 7.27-7.23 (m, 2H),7.08-7.04 (m, 2H), 6.89-6.85 (m, 2H), 3.87 (d, J=13.36 Hz, 2H), 3.80 (s,3H), 3.26 (s, 1H), 3.18 (s, 3H), 2.78-2.72 (m, 2H), 2.40 (s, 3H),1.68-1.66 (m, 2H).

Example 6 4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid(4-methoxy-phenyl)methyl-amide (“A6”)

The compound is prepared analogously to example 1.

Yield: 8 mg (16%); LCMS (Method A): 383.3 (M+H), Rt. 4.43 min, purity99.7% (254 nm); HPLC (Method A): Rt. 4.42 min, 99.7% (254 nm);

¹H NMR (400 MHz, CDCl₃): δ 7.88 (dd, J=8.92 Hz, 2H), 7.06 (dd, J=9.00Hz, 2H), 6.92 (dd, J=8.92 Hz, 2H), 6.87 (dd, J=8.96 Hz, 2H), 3.90-3.82(m, 5H), 3.80 (s, 3H), 3.27-3.21 (m, 1H), 3.18 (s, 3H), 2.78-2.71 (m,2H), 1.68-1.55 (m, 2H), 1.53-1.47 (m, 2H).

Example 7 4-(3-fluoro-benzoyl)-piperidine-1-carboxylic acid(4-methoxy-phenyl)-methylamide (“A7”)

The compound is prepared analogously to example 1.

Yield: 77 mg (17%); LCMS (Method A): 371.3 (M+H), Rt. 4.59 min, purity98.3% (254 nm); HPLC (Method A): Rt. 4.76 min, 98.2% (254 nm);

¹H NMR (400 MHz, CDCl₃): δ 7.67-7.65 (m, 1H), 7.58-7.55 (m, 1H),7.46-7.41 (m, 1H), 7.27-7.23 (m, 1H), 7.09-7.04 (m, 2H), 6.90-6.86 (m,2H), 3.89-3.86 (m, 2H), 3.81 (s, 3H), 3.26-3.20 (m, 4H), 2.79-2.72 (m,2H), 1.70-1.64 (m, 2H), 1.55-1.45 (m, 2H).

Example 8 4-(4-fluoro-benzoyl)-piperidine-1-carboxylic acid(4-methoxy-phenyl)-methylamide (“A8”)

The compound is prepared analogously to example 1.

Yield: 8 mg (16%); LCMS (Method A): 371.2 (M+H), Rt. 4.63 min, purity99.6% (254 nm); HPLC (Method A): Rt. 4.60 min, 99.8% (254 nm);

¹H NMR (400 MHz, CDCl₃): δ 7.94-7.90 (m, 2H), 7.13 (t, J=8.64 Hz, 2H),7.10 (d, J=2.04 Hz, 2H), 6.89-6.87 (m, 2H), 3.90-3.86 (m, 2H), 3.81 (s,3H), 3.27-3.21 (m, 1H), 3.18 (s, 3H), 2.76 (t, J=14.44 Hz, 2H),1.69-1.65 (m, 2H), 1.55-1.49 (m, 2H).

Example 9 4-(4-chloro-benzoyl)-piperidine-1-carboxylic acid(4-methoxy-phenyl)-methylamide (“A9”)

The compound is prepared analogously to example 1.

Yield: 183 mg (16%); LCMS (Method A): 387.0 (M+H), Rt. 4.93 min, purity99.5% (254 nm); HPLC (Method A): Rt. 4.90 min, 99.6% (254 nm);

¹H NMR (400 MHz, CDCl₃): δ 7.84-7.81 (m, 2H), 7.44-7.41 (m, 2H),7.07-7.05 (m, 2H), 6.89-6.87 (m, 2H), 3.87 (t, J=13.32 Hz, 2H), 3.81 (s,3H), 3.26-3.18 (m, 1H), 3.07 (s, 3H), 2.79-2.72 (m, 2H), 1.70-1.54 (m,2H), 1.52-1.48 (m, 2H).

Example 10 4-benzoyl-piperidine-1-carboxylic acid(3-cyano-phenyl)-methyl-amide (“A10”)

The compound is prepared analogously to example 1.

Yield: 4 mg (2%); LCMS (Method A): 405.2 (M+H), Rt. 4.76 min, purity96.8% (254 nm); HPLC (Method A): Rt. 4.34 min, 94.9% (254 nm);

¹H NMR (400 MHz, DMSO-d₆): δ 7.98-7.96 (m, 2H), 7.62-7.44 (m, 7H), 3.85(t, J=10.56 Hz, 2H), 3.61-3.56 (m, 1H), 3.24 (s, 3H), 2.95 (t, J=13.36Hz, 2H), 1.78-1.58 (m, 2H), 1.57-1.41 (m, 2H).

Example 11 4-benzoyl-piperidine-1-carboxylic acid(4-cyano-phenyl)-methyl-amide (“A11”)

The compound is prepared analogously to example 1.

Yield: 12 mg (5%); LCMS (Method A): 348.0 (M+H), Rt. 4.30 min, purity98.6% (254 nm); HPLC (Method A): Rt. 4.46 min, 94.9% (254 nm);

¹H NMR (400 MHz, DMSO-d₆): δ 7.98-7.96 (m, 2H), 7.75-7.74 (m, 2H), 7.63(t, J=13.48 Hz, 1H), 7.52 (t, J=15.20 Hz, 1H), 7.17-7.14 (m, 2H),3.80-3.76 (m, 2H), 3.66-3.61 (m, 1H), 3.14 (s, 3H), 2.95 (t, J=12.52 Hz,2H), 1.76-1.73 (m, 2H), 1.49-1.39 (m, 2H).

Example 12 4-benzoyl-piperidine-1-carboxylic acid(3-fluoro-phenyl)-methyl-amide (“A12”)

The compound is prepared analogously to example 1.

Yield: 23 mg (10%); LCMS (Method A): 341.3 (M+H), RT. 4.68 min, purity99% (254 nm); HPLC (Method B): Rt. 6.09 min, 94.7% (254 nm);

¹H NMR (400 MHz, CDCl₃): δ 7.91-7.89 (m, 2H), 7.57 (t, J=9.16 Hz, 1H),7.46 (t, J=15.12 Hz, 2H), 7.32-7.27 (m, 1H), 6.90-6.88 (m, 1H),6.85-6.79 (m, 2H), 3.91-3.86 (m, 2H), 3.36-3.32 (m, 1H), 3.24 (s, 3H),2.87-2.80 (m, 2H), 1.78-1.74 (m, 2H), 1.66-1.63 (m, 1H), 1.62-1.56 (m,2H).

Example 13 4-benzoyl-piperidine-1-carboxylic acid(4-fluoro-phenyl)-methyl-amide (“A13”)

The compound is prepared analogously to example 1.

Yield: 26 mg (11%); LCMS (Method A): 341.2 (M+H), Rt. 4.70 min, purity98.8% (254 nm); HPLC (Method A): Rt. 4.61 min, 98.6% (254 nm);

¹H NMR (400 MHz, DMSO-d₆): δ 7.94 (d, J=7.60 Hz, 2H), 7.61 (t, J=14.68Hz, 1H), 7.50 (t, J=15.32 Hz, 2H), 7.19-7.17 (m, 4H), 3.71-3.68 (m, 2H),3.55-3.49 (m, 1H), 3.05 (s, 3H), 2.76 (t, J=23.28 Hz, 2H), 1.62-1.59 (m,2H), 1.32-1.22 (m, 2H).

Example 14 4-benzoyl-piperidine-1-carboxylic acidethyl-(4-methoxy-phenyl)-amide (“A14”)

The compound is prepared analogously to example 1.

Yield: 103 mg (42%); LCMS (Method A): 367.2 (M+H), Rt. 4.82 min, purity100% (254 nm); HPLC (Method A): Rt. 4.75 min, 100% (254 nm);

¹H NMR (400 MHz, DMSO-d₆): δ 7.92 (d, J=7.44 Hz, 2H), 7.61 (t, J=14.72Hz, 1H), 7.49 (t, J=15.40 Hz, 2H), 7.06 (d, J=1.96 Hz, 2H), 6.93 (d,J=3.32 Hz, 2H), 3.73 (s, 3H), 3.69-3.66 (m, 2H), 3.51-3.46 (m, 3H), 2.68(t, J=23.16 Hz, 2H), 1.57-1.54 (m, 2H), 1.23-1.20 (m, 2H), 0.99-0.95 (m,3H).

Example 15 4-benzoyl-piperidine-1-carboxylic acid(2-hydroxy-ethyl)-(4-methoxy-phenyl)amide (“A15”)

The compound is prepared analogously to example 1, purification viapreparative HPLC; yield: 13 mg (17%); LCMS (Method A): 383.2 (M+H), Rt.4.07 min, purity 98.2% (254 nm); HPLC (Method A): Rt. 4.04 min, 98% (254nm)

¹H NMR (400 MHz, DMSO-d₆): δ 7.91-7.93 (m, 2H), 7.59-7.63 (m, 1H),7.48-7.51 (m, 2H), 7.09 (dd, J=2.20, 6.74 Hz, 2H), 6.91 (dd, J=2.16,6.78 Hz, 2H), 4.74 (t, J=5.20 Hz, 1H), 3.73 (s, 3H), 3.67-3.70 (m, 2H),3.51-3.54 (m, 2H), 3.42 (q, J=12.16 Hz, 2H), 2.66-2.71 (m, 2H),1.54-1.57 (m, 2H), 1.21-1.27 (m, 2H).

Example 16 (4-benzoyl-piperidin-1-yl)-(2,3-dihydro-indol-1-yl)-methanone(“A16”)

The compound is prepared analogously to example 1.

Yield: 59 mg (26%); LCMS (Method A): 335.2 (M+H), Rt. 4.78 min, purity98.5% (254 nm); HPLC (Method A): Rt. 4.74 min, 98.5% (254 nm);

¹H NMR (400 MHz, DMSO-d₆): δ 8.01 (d, J=8.48 Hz, 2H), 7.65 (t, J=14.72Hz, 1H), 7.54 (t, J=15.16 Hz, 2H), 7.18 (d, J=7.20 Hz, 1H), 7.12 (t,J=15.24 Hz, 1H), 6.99 (d, J=7.88 Hz, 1H), 6.85 (t, J=14.56 Hz, 1H), 3.82(t, J=16.56 Hz, 2H), 3.67-3.76 (m, 3H), 2.96-3.09 (m, 4H), 1.81 (d,J=11.20 Hz, 2H), 1.55-1.64 (m, 2H).

Example 17(2,3-dihydro-indol-1-yl)-[4-(4-methyl-benzoyl)-piperidin-1-yl]-methanone(“A17”)

The compound is prepared analogously to example 1.

Yield: 221 mg (52%); LCMS (Method A): 349.2 (M+H), Rt. 5.11 min, purity98.6% (254 nm); HPLC (Method A): Rt. 5.05 min, 97.2% (254 nm);

¹H NMR (400 MHz, CDCl₃): δ 7.87 (d, J=8.24 Hz, 2H), 7.29 (d, J=8.04 Hz,2H), 7.19-7.14 (m, 2H), 7.07-7.05 (m, 1H), 6.92-6.88 (m, 1H), 3.96-3.89(m, 4H), 3.50-3.44 (m, 1H), 3.08-3.01 (m, 4H), 2.43 (s, 3H), 1.94-1.86(m, 4H).

Example 18(2,3-dihydro-indol-1-yl)-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-methanone(“A18”)

The compound is prepared analogously to example 1.

Yield: 8 mg (16%); LCMS (Method A): 365.0 (M+H), Rt. 4.70 min, purity99.9% (254 nm); HPLC (Method A): Rt. 4.71 min, 99.7% (254 nm);

¹H NMR (400 MHz, CDCl₃): δ 7.97 (d, J=8.92 Hz, 2H), 7.20-7.14 (m, 2H),7.07 (d, J=7.92 Hz, 1H), 6.97 (d, J=11.76 Hz, 2H), 6.90 (d, J=14.72 Hz,1H), 3.97-3.89 (m, 7H), 3.45 (t, J=14.36 Hz, 1H), 1.93-1.88 (m, 4H).

Example 19(2,3-dihydro-indol-1-yl)-[4-(3-fluoro-benzoyl)-piperidin-1-yl]-methanone(“A19”)

The compound is prepared analogously to example 1.

Yield: 60 mg (14%); LCMS (Method A): 353.2 (M+H), Rt. 5.01 min, purity96.8% (254 nm); HPLC (Method A): Rt. 5.19 min, 96.9% (254 nm);

¹H NMR (400 MHz, CDCl₃): δ 7.75 (d, J=7.76 Hz, 1H), 7.67-7.63 (m, 1H),7.51-7.46 (m, 1H), 7.32-7.28 (m, 1H), 7.20-7.14 (m, 2H), 7.06 (d, J=7.92Hz, 1H), 6.91 (t, J=14.72 Hz, 1H), 3.97-3.90 (m, 4H), 3.50-3.41 (m, 1H),3.09-3.02 (m, 4H), 1.96-1.87 (m, 4H).

Example 20(2,3-dihydro-indol-1-yl)-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-methanone(“A20”)

The compound is prepared analogously to example 1.

Yield: 8 mg (16%); LCMS (Method A): 353.2 (M+H), Rt. 4.93 min, purity98.9% (254 nm); HPLC (Method A): Rt. 5.19 min, 96.9% (254 nm);

¹H NMR (400 MHz, CDCl₃): δ 8.03-7.99 (m, 2H), 7.20-7.15 (m, 4H), 7.06(d, J=7.88 Hz, 2H), 6.93-6.89 (m, 1H), 3.97-3.90 (m, 4H), 3.47-3.43 (m,1H), 3.08-3.02 (m, 4H), 1.93-1.88 (m, 4H).

Example 21[4-(4-chloro-benzoyl)-piperidin-1-yl]-(2,3-dihydro-indol-1-yl)-methanone(“A21”)

The compound is prepared analogously to example 1.

Yield: 108 mg (26%); LCMS (Method A): 369.0 (M+H), Rt. 5.18 min, purity98% (254 nm); HPLC (Method A): Rt. 5.19 min, 96.9% (254 nm);

¹H NMR (400 MHz, CDCl₃): δ 7.92-7.90 (m, 2H), 7.49-7.46 (m, 2H),7.27-7.14 (m, 2H), 7.06 (d, J=7.84 Hz, 1H), 6.93-6.89 (m, 1H), 3.97-3.89(m, 4H), 3.50-3.42 (m, 1H), 3.08-3.01 (m, 4H), 1.93-1.61 (m, 4H).

Example 22(4-benzoyl-piperidin-1-yl)-(3,4-dihydro-2H-quinolin-1-yl)-methanone(“A22”)

The compound is prepared analogously to example 1.

Yield: 8 mg (16%); LCMS (Method A): 349.2 (M+H), Rt. 4.85 min, purity97.3% (254 nm); HPLC (Method A): Rt. 4.84 min, 97.6% (254 nm);

¹H NMR (400 MHz, DMSO-d₆): δ 7.98 (t, J=8.52 Hz, 2H), 7.64 (t, J=13.64Hz, 1H), 7.53 (t, J=15.20 Hz, 2H), 7.08-7.04 (m, 2H), 6.92 (d, J=7.92Hz, 1H), 6.87-6.83 (m, 1H), 3.77 (d, J=13.16 Hz, 2H), 3.64-3.54 (m, 1H),3.47-3.44 (m, 2H), 2.99-2.92 (m, 2H), 2.73-2.66 (m, 2H), 1.88-1.83 (m,2H), 1.76-1.73 (m, 2H), 1.54-1.44 (m, 2H).

Example 23 Synthesis of4-(4-methoxy-3-methyl-benzoyl)-piperidine-1-carboxylic acid(4-methoxy-phenyl)-methyl-amide (“A23”) 23.1 piperidine-1,4-dicarboxylicacid mono-tert-butyl ester

To a solution of piperidine-4-carboxylic acid (20.00 g, 150.20 mmol) inwater (200 mL) was added sodium hydroxide (18.21 g, 450.61 mmol)followed by BOC anhydride (38.34 ml, 165.23 mmol) at 0° C. dropwise. Thereaction mixture was stirred at room temperature for 16 h and acidifiedwith 10% citric acid. The solids precipitated out were collected byfiltration, washed with water (100 mL) and dried under suction; yield:25.0 g (72%), colorless solid (crude product);

¹H NMR (400 MHz, DMSO-d₆): δ 3.82 (d, J=13.0 Hz, 2H), 2.90-2.75 (m, 2H),2.42-2.35 (m, 1H), 1.77 (dd, J=3.1, 13.3 Hz, 2H), 1.41 (s, 9H),1.40-1.35 (m, 2H);

LC/MS (Method A): 130.2 (M+H; BOC-cleaved mass), Rt. 3.29 min, purity99%.

23.2 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acidtert-butyl ester

To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester(25.00 g, 107.72 mmol) in DMF (250 mL) were added N,N-diisopropylethylamine (57.01 mL, 323.16 mmol), 1-hydroxybenzotriazole hydrate (1.67g, 10.77 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimidehydrochloride (25.03 g, 129.27 mmol) followed by the addition ofO,N-dimethyl-hydroxylamine hydrochloride (11.68 g, 118.49 mmol) in smallportions at 0° C. under nitrogen atmosphere. The reaction mixture wasstirred at room temperature for 18 h. After completion of the reactionthe solvent was evaporated under reduced pressure. The residue wasdissolved in ethyl acetate (300 mL), washed with 10% sodium bicarbonate(2×200 mL), 0.5 N HCl (2×100 mL), water (200 mL) and brine (200 mL). Theorganic layer was dried over anhydrous Na₂SO₄ and evaporated undervacuum; yield: 24.0 g (81%), colorless liquid (crude product);

¹H NMR (400 MHz, CDCl₃): δ 4.15-4.09 (m, 2H), 3.70 (s, 3H), 3.17 (s,3H), 2.79-2.72 (m, 3H), 1.72-1.60 (m, 4H), 1.44 (s, 9H);

LC/MS (Method A): 173.2 (M+H; BOC-cleaved mass), Rt. 3.54 min, purity99%.

23.3 4-(4-methoxy-3-methyl-benzoyl)-piperidine-1-carboxylic acidtert-butyl ester

Iodine (0.93 mg) and 5 mL of 4-bromo-2-methyl anisole (5.96 g, 29.06mmol) dissolved in THF (40 mL) were added to a suspension of magnesiumturnings (0.72 g, 29.06 mmol) in dry THF (40 mL) under nitrogenatmosphere. The mixture was stirred at room temperature for 15 min andthen warmed up to 50° C. The mixture was cooled to room temperature andremaining solution of 4-Bromo-2-methyl anisole in THF was added dropwiseduring a period of 20 min. The mixture was stirred for additional 2 h atroom temperature to complete dissolution of magnesium. This grignardreagent solution was added dropwise to a solution of4-(Methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butylester (4.00 g, 14.53 mmol) in THF (40.00 mL) at −78° C. The reactionmixture was allowed to stir at room temperature for 15 h. Then it wascooled to 0° C., quenched by saturated ammonium chloride solution (100mL) and extracted with ethyl acetate (2×100 mL). The organic layer waswashed with 10% sodium bicarbonate (100 mL), water (100 mL) and brine(100 mL), dried over anhydrous Na₂SO₄ and evaporated under vacuum. Thecrude material was purified by flash chromatography using silica gel(230-400) and petrol ether/ethyl acetate (0-30%) as a gradient elution;yield: 1.50 g (30%);

¹H NMR (400 MHz, CDCl₃): δ 7.82 (dd, J=2.2, 8.6 Hz, 1H), 7.76 (d, J=1.6Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 4.17 (d, J=13.0 Hz, 2H), 3.90 (s, 3H),3.41-3.34 (m, 1H), 2.93-2.86 (m, 2H), 2.26 (s, 3H), 1.83-1.80 (m, 2H),1.76-1.65 (m, 2H), 1.45 (s, 9H);

LC/MS (Method A): 234.3 (M+H; BOC-cleaved mass), Rt. 5.31 min, purity99%.

23.4 (4-methoxy-3-methyl-phenyl)-piperidin-4-yl-methanone hydrochloride

A solution of 4-(4-methoxy-3-methyl-benzoyl)-piperidine-1-carboxylicacid tert-butyl ester (1.50 g, 4.36 mmol) in dioxane/HCl (3M, 14.53 ml,43.60 mmol) was stirred at room temperature for 6 h under nitrogenatmosphere. The solvent was evaporated to dryness under reduced pressureto afford the title compound; yield: 1.10 g (92% crude product);

¹H NMR (400 MHz, DMSO-d₆): δ 9.25 (brs, 1H), 8.92 (brs, 1H), 7.90 (dd,J=2.2, 8.6 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.05 (d, J=8.6 Hz, 1H), 3.87(s, 3H), 3.75-3.67 (m, 1H), 3.29-3.25 (m, 2H), 3.06-2.97 (m, 2H), 2.19(s, 3H), 1.89-1.86 (m, 2H), 1.81-1.78 (m, 2H);

LC/MS (Method A): 234.3 (M+H), Rt. 2.65 min, purity 98%.

23.5 4-(4-methoxy-3-methyl-benzoyl)-piperidine-1-carboxylic acid(4-methoxy-phenyl)-methyl-amide (“A23”)

To a solution 4-methoxy-N-methyl aniline (0.28 g, 2.01 mmol) in DCM (10mL) was added ethyl-diisopropyl-amine (1.61 mL, 9.15 mmol) followed bytriphosgene (0.66 g, 2.20 mmol) at 0° C. under nitrogen atmosphere.After being stirred for 1 h at 0° C.,(4-methoxy-3-methyl-phenyl)-piperidin-4-yl-methanone hydrochloride (0.50g, 1.83 mmol) was added and stirred at room temperature for 16 h. Thereaction was diluted with DCM (100 mL), washed with water (100 mL), 10%sodium bicarbonate (2×100 mL), brine (100 mL), dried over anhydrousNa₂SO₄ and evaporated under vacuum. The crude material was purified byflash column using silica gel (230-400) and petrol ether/ethyl acetate(0-40%) as eluent; yield: 60 mg (8%);

¹H NMR (400 MHz, DMSO-d₆): δ 7.82 (dd, J=2.1, 8.6 Hz, 1H), 7.73 (d,J=1.5 Hz, 1H), 7.06 (dd, J=2.2, 6.8 Hz, 2H), 7.00 (d, J=8.6 Hz, 1H),6.91 (dd, J=2.1, 6.8 Hz, 2H), 3.84 (s, 3H), 3.74-3.69 (m, 5H), 3.46-3.40(m, 1H), 3.01 (s, 3H), 2.73-2.67 (m, 2H), 2.16 (s, 3H), 1.55-1.52 (m,2H), 1.29-1.19 (m, 2H);

LC/MS (Method A): 397 (M+H), Rt. 4.76 min, purity 100%.

Example 24 4-(4-methoxy-3-methyl-benzoyl)-piperidine-1-carboxylic acidethyl-(4-methoxy-phenyl)-amide (“A24”)

The compound is prepared analogously to example 22 fromethyl-(4-methoxy-phenyl)-amine (0.31 g, 2.01 mmol),ethyl-diisopropyl-amine (1.61 ml, 9.15 mmol), triphosgene (0.66 g, 2.20mmol) and (4-methoxy-3-methyl-phenyl)piperidin-4-yl-methanonehydrochloride (0.50 g, 1.83 mmol) in DCM (10 mL); Purification:preparative HPLC; yield: 40 mg (5%);

¹H NMR (400 MHz, DMSO-d₆): δ 7.81 (dd, J=2.2, 8.6 Hz, 1H), 7.73 (d,J=1.5 Hz, 1H), 7.05-6.99 (m, 3H), 6.94-6.90 (m, 2H), 3.84 (s, 3H), 3.73(s, 3H), 3.69-3.66 (m, 2H), 3.51-3.41 (m, 3H), 2.67 (t, J=12.5 Hz, 2H),2.16 (s, 3H), 1.52-1.50 (m, 2H), 1.26-1.16 (m, 2H), 0.97 (t, J=6.96 Hz,3H);

LC/MS (Method A): 411 (M+H), Rt. 5.06 min, purity 100%.

Example 25 25.1 piperidin-4-yl-m-tolyl-methanone hydrochloride

The compound is prepared analogously to example 23.1.-23.4.

Yield: 2.80 g (95% crude product);

¹H NMR (400 MHz, DMSO-d₆): δ 9.27 (brs, 1H), 8.98 (brs, 1H), 7.80 (d,J=8.4 Hz, 2H), 7.48-7.40 (m, 2H), 3.79-3.71 (m, 1H), 3.27 (d, J=12.6 Hz,2H), 3.06-2.97 (m, 2H), 2.38 (s, 3H), 1.92-1.89 (m, 2H), 1.81-1.74 (m,2H);

LC/MS (Method A): 204.3 (M+H), Rt. 2.48 min, purity 100%.

25.2 4-(3-methyl-benzoyl)-piperidine-1-carboxylic acid(4-methoxy-phenyl)methyl-amide (“A25”)

Preparation as described for example 22 from 4-methoxy-N-methyl aniline(0.32 g, 2.27 mmol), ethyl-diisopropyl-amine (1.82 ml, 10.33 mmol),triphosgene (0.75 g, 2.48 mmol) and piperidin-4-yl-m-tolyl-methanonehydrochloride (0.50 g, 2.07 mmol) in DCM (10 mL).

Purification: Flash column chromatography using silica gel (230-400) andpetrol ether/ethyl acetate (0-30%) as eluent; yield: 100 mg (13%);

¹H NMR (400 MHz, DMSO-d₆): δ 7.73-7.71 (m, 2H), 7.43-7.35 (m, 2H), 7.06(dd, J=2.2, 6.8 Hz, 2H), 6.91 (dd, J=2.2, 6.8 Hz, 2H), 3.73-3.69 (m,5H), 3.50-3.44 (m, 1H), 3.01 (s, 3H), 2.71 (t, J=12.2 Hz, 2H), 2.35 (s,3H), 1.57 (d, J=11.1 Hz, 2H), 1.29-1.19 (m, 2H);

LC/MS (Method A): 367 (M+H), Rt. 4.76 min, purity 97%.

Example 26 4-(3-methyl-benzoyl)-piperidine-1-carboxylic acidethyl-(4-methoxy-phenyl)amide (“A26”)

The compound is prepared analogously to example 22 fromethyl-(4-methoxy-phenyl)-amine (0.35 g, 2.27 mmol),ethyl-diisopropyl-amine (1.82 ml, 10.33 mmol), triphosgene (0.75 g, 2.48mmol) and piperidin-4-yl-m-tolyl-methanone hydrochloride (0.50 g, 2.07mmol) in DCM (10 mL).

Purification: Flash column chromatography using silica gel (230-400) andpetrol ether/ethyl acetate (0-30%) as eluent; yield: 30 mg (4%);

¹H NMR (400 MHz, DMSO-d₆): δ 7.72-7.70 (m, 2H), 7.43-7.35 (m, 2H), 7.04(dd, J=2.2, 6.7 Hz, 2H), 6.92 (dd, J=2.2, 6.7 Hz, 2H), 3.73 (s, 3H),3.69-3.66 (m, 2H), 3.51-3.42 (m, 3H), 2.67 (t, J=12.4 Hz, 2H), 2.35 (s,3H), 1.56-1.53 (m, 2H), 1.26-1.17 (m, 2H), 0.97 (t, J=6.92 Hz, 3H);LC/MS (Method A): 381.2 (M+H), %; Rt. 5.05 min, purity 97%.

Example 27 4-(3-methoxy-benzoyl)-piperidine-1-carboxylic acid(4-methoxy-phenyl)methyl-amide (“A27”)

The compound is prepared analogously to example 22 from4-methoxy-N-methyl aniline (0.30 g, 2.15 mmol), ethyl-diisopropyl-amine(1.72 ml, 9.76 mmol), triphosgene (0.71 g, 2.34 mmol) and(3-methoxy-phenyl)-piperidin-4-yl-methanone hydrochloride (0.50 g, 1.95mmol) in DCM (10 mL).

Purification: Flash column chromatography using silica gel (230-400) andpetrol ether/ethyl acetate (0-40%) as eluent; yield: 160 mg (21%);

¹H NMR (400 MHz, DMSO-d₆): δ 7.53 (d, J=7.7 Hz, 1H), 7.43-7.38 (m, 2H),7.18 (dd, J=2.6, 8.1 Hz, 1H), 7.06 (dd, J=2.1, 6.7 Hz, 2H), 6.91 (dd,J=2.2, 6.8 Hz, 2H), 3.79 (s, 3H), 3.73-3.68 (m, 5H), 3.52-3.45 (m, 1H),3.01 (s, 3H), 2.72 (t, J=12.2 Hz, 2H), 1.58-1.56 (m, 2H), 1.29-1.19 (m,2H). LC/MS (Method A): 383.2 (M+H), Rt. 4.52 min, 100%.

Example 28 4-(3-methoxy-benzoyl)-piperidine-1-carboxylic acidethyl-(4-methoxy-phenyl)amide (“A28”)

The compound is prepared analogously to example 22 fromethyl-(4-methoxy-phenyl)-amine (0.33 g, 2.15 mmol),ethyl-diisopropyl-amine (1.72 ml, 9.76 mmol), triphosgene (0.71 g, 2.34mmol) and (3-methoxy-phenyl)-piperidin-4-yl-methanone hydrochloride(0.50 g, 1.95 mmol) in DCM (10 mL).

Purification: preparative HPLC; yield: 17 mg (22%);

¹H NMR (400 MHz, DMSO-d₆): δ 7.52 (d, J=7.7 Hz, 1H), 7.43-7.37 (m, 2H),7.18 (dd, J=2.5, 8.1 Hz, 1H), 7.04 (dd, J=2.1, 6.8 Hz, 2H), 6.92 (dd,J=2.1, 6.9 Hz, 2H), 3.78 (s, 3H), 3.73 (s, 3H), 3.67 (d, J=13.1 Hz, 2H),3.51-3.43 (m, 3H), 2.71-2.65 (m, 2H), 1.56-1.53 (m, 2H), 1.26-1.16 (m,2H), 0.99-0.97 (m, 3H);

LC/MS (Method A): 397 (M+H), Rt. 4.81 min, purity 99%.

Example 29 4-(3-fluoro-4-methoxy-benzoyl)-piperidine-1-carboxylic acid(4-methoxy-phenyl)-methyl-amide (“A29”)

The compound is prepared analogously to example 22 from4-methoxy-N-methyl aniline (0.28 g, 1.97 mmol), ethyl-diisopropyl-amine(1.57 ml, 8.93 mmol), triphosgene (0.65 g, 2.14 mmol) and(3-fluoro-4-methoxy-phenyl)piperidin-4-yl-methanone hydrochloride (0.50g, 1.79 mmol) in DCM (10 mL).

Purification: Flash column chromatography using silica gel (230-400) andpetrol ether/ethyl acetate (0-40%) as eluent; yield: 250 mg (34%);

¹H NMR (400 MHz, DMSO-d₆): δ 7.82-7.73 (m, 2H), 7.25 (t, J=8.6 Hz, 1H),7.06 (dd, J=2.2, 6.8 Hz, 2H), 6.91 (dd, J=2.2, 6.8 Hz, 2H), 3.90 (s,3H), 3.73-3.68 (m, 5H), 3.49-3.40 (m, 1H), 3.01 (s, 3H), 2.71 (t, J=12.2Hz, 2H), 1.55 (d, J=11.1 Hz, 2H), 1.25-1.22 (m, 2H);

LC/MS (Method A): 401.2 (M+H), Rt. 4.55 min, purity 97%.

Example 30 Synthesis of4-{4-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-benzoyl}-piperidine-1-carboxylicacid (4-methoxy-phenyl)-methyl-amide (“A30”) 30.1(4-bromo-phenyl)-piperidin-4-yl-methanone

A mixture of 1-acetyl-piperidine-4-carboxylic acid (10.00 g, 57.24 mmol)and thionyl chloride (20.85 g, 171.73 mmol) was stirred at roomtemperature for 6 h under nitrogen atmosphere. Thionyl chloride wasremoved under reduced pressure and the residue was co-distilled with DCM(2×200 mL). This acid chloride was then added dropwise to a suspensionof bromobenzene (27.24 g, 171.73 mmol) and anhydrous aluminum chloride(9.25 g, 68.69 mmol) in DCE (200 mL) at 0° C. under nitrogen atmosphere.The resulting mixture was stirred at room temperature for 16 h, quenchedto ice and extracted with DCM (2×200 mL). The organic layer was washedwith water (2×200 mL), brine (200 mL), dried over anhydrous Na₂SO₄ andevaporated under vacuum. The resulting black residue was taken in 6M HCl(200 mL), refluxed for 12 h and concentrated to half of its originalvolume. The aqueous part was basified with 10% sodium bicarbonate andextracted with DCM (2×200 mL), washed with water (2×200 mL), brine (200mL), dried over anhydrous Na₂SO₄ and evaporated under vacuum. The crudematerial was purified by column chromatography using silica gel (60-120)and DCM/methanol as gradient elution; yield: 3.50 g (21%);

¹H NMR (400 MHz, DMSO-d₆): δ 7.95-7.92 (m, 2H), 7.78-7.74 (m, 2H),3.71-3.68 (m, 1H), 3.25-3.22 (m, 2H), 2.98-2.92 (m, 2H), 1.90-1.87 (m,2H), 1.76-1.70 (m, 2H);

LC/MS (Method A): 268/270 (M+H), Rt. 2.73 min, purity 93%.

30.2 4-(4-bromo-benzoyl)-piperidine-1-carboxylic acid(4-methoxy-phenyl)methyl-amide

The compound is prepared analogously to example 22 from4-methoxy-N-methyl aniline (0.81 g, 5.78 mmol), ethyl-diisopropyl-amine(4.62 ml, 26.28 mmol), triphosgene (1.91 g, 6.31 mmol) and(4-bromo-phenyl)-piperidin-4-yl-methanone (1.50 g, 5.26 mmol) in DCM (30mL).

Purification: Flash column chromatography using silica gel (230-400) andpetrol ether/ethyl acetate (0-30%) as eluent; yield: 1.10 g (46%);

¹H NMR (400 MHz, CDCl₃): δ 7.75 (dd, J=1.9, 6.7 Hz, 2H), 7.59 (dd,J=2.0, 6.7 Hz, 2H), 7.06 (dd, J=2.2, 6.7 Hz, 2H), 6.87 (dd, J=2.3, 6.7Hz, 2H), 3.89-3.85 (m, 2H), 3.80 (s, 3H), 3.23-3.21 (m, 1H), 3.18 (s,3H), 2.78-2.71 (m, 2H), 1.68-1.64 (m, 2H), 1.51-1.47 (m, 2H), 1.28-1.24(m, 2H);

LC/MS (Method A): 431/433 (M+H), Rt. 4.99 min, purity 94%.

30.34-{4-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-benzoyl}-piperidine-1-carboxylicacid (4-methoxy-phenyl)-methyl-amide (“A30”)

A solution of 4-(4-bromo-benzoyl)-piperidine-1-carboxylic acid(4-methoxy-phenyl)-methyl-amide (100.0 mg, 0.22 mmol),1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(93.5 mg, 0.24 mmol) and cesium carbonate (216 mg, 0.66 mmol) in dioxane(2 mL)/water (0.20 mL) was degassed for 5 min.1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane (18.43 mg, 0.02 mmol) was then added and refluxed for 16h under nitrogen atmosphere. The reaction was cooled to room temperatureand filtered through celite. The filtrate was evaporated under vacuum.The residue was dissolved in ethyl acetate (50 mL), washed with water(50 mL) and brine (50 mL), dried over anhydrous Na₂SO₄ and evaporatedunder vacuum. The crude material was purified by preparative HPLC;yield: 69 mg (62%);

¹H NMR (400 MHz, DMSO-d₆): δ 8.29 (s, 1H), 8.00 (s, 1H), 7.91 (d, J=8.4Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 7.07 (dd, J=2.0, 6.9 Hz, 2H), 6.92 (dd,J=2.0, 6.9 Hz, 2H), 4.27 (t, J=5.2 Hz, 2H), 3.73-3.69 (m, 7H), 3.55-3.45(m, 1H), 3.22 (s, 3H), 3.01 (s, 3H), 2.72 (t, J=12.08 Hz, 2H), 1.59-1.56(m, 2H), 1.31-1.21 (m, 2H);

LC/MS (Method A): 477.2 (M+H), Rt. 4.2 min, purity 93%.

Example 31 31.1 4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid(4-bromo-phenyl)methyl-amide

The compound is prepared analogously to example 22 from(4-bromo-phenyl)methyl-aniline (1.96 g, 10.22 mmol),ethyl-diisopropyl-amine (6.06 g, 46.43 mmol), triphosgene (3.37 g, 11.14mmol) and (4-methoxy-phenyl)-piperidin-4-yl-methanone hydrochloride(2.50 g, 9.29 mmol) in DCM (50 mL). Purification: Flash columnchromatography using silica gel (230-400) and petrol ether/ethyl acetate(0-40%) as eluent; yield: 1.70 g (41%);

¹H NMR (400 MHz, CDCl₃): δ 7.89 (dd, J=2.0, 9.3 Hz, 2H), 7.45 (dd,J=2.0, 6.8 Hz, 2H), 6.99 (dd, J=2.1, 6.8 Hz, 2H), 6.93 (d, J=8.9 Hz,2H), 3.89 (s, 3H), 3.87-3.84 (m, 2H), 3.32-3.25 (m, 1H), 3.21 (s, 3H),2.83-2.76 (m, 2H), 1.74-1.69 (m, 2H), 1.64-1.53 (m, 3H);

LC/MS (Method A): 430/432 (M+H), Rt. 4.98 min, purity 98%.

31.2 4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid{4-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-phenyl}-methyl-amide (“A31”)

The compound is prepared analogously to example 29 from4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid(4-bromo-phenyl)-methyl-amide (100.0 mg, 0.23 mmol),1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(96.4 mg; 0.25 mmol), cesium carbonate (222.8 mg, 0.68 mmol) and1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane (1.90 mg) in dioxane/water.

Purification: preparative HPLC; yield: 14 mg (13%);

¹H NMR (400 MHz, DMSO-d₆): δ 8.12 (s, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.85(s, 1H), 7.54 (d, J=8.5 Hz, 2H), 7.10 (d, J=8.5 Hz, 2H), 7.00 (d, J=8.9Hz, 2H), 4.25 (t, J=5.2 Hz, 2H), 3.81 (s, 3H), 3.75-3.68 (m, 4H),3.49-3.42 (m, 1H), 3.23 (s, 3H), 3.08 (s, 3H), 2.76 (t, J=12.12 Hz, 2H),1.59-1.56 (m, 2H), 1.36-1.27 (m, 2H);

LC/MS (Method A): 477.2 (M+H), Rt. 4.16 min, purity 95%.

Example 32 32.1 4-(4-bromo-benzoyl)-piperidine-1-carboxylic acid(4-bromo-phenyl)methyl-amide

The compound is prepared analogously to example 22 from(4-bromo-phenyl)methyl-aniline (1.11 g, 5.78 mmol),ethyl-diisopropyl-amine (4.62 ml, 26.28 mmol), triphosgene (1.91 g, 6.31mmol) and (4-bromo-phenyl)-piperidin-4-yl-methanone (1.50 g, 5.26 mmol)in DCM (30 mL).

Purification: Flash column chromatography using silica gel (230-400) andpetrol ether/ethyl acetate (0-30%) as eluent; yield: 1.20 g (45%);

¹H NMR (400 MHz, CDCl₃): δ 7.76 (dd, J=1.9, 6.7 Hz, 2H), 7.60 (dd,J=2.0, 6.7 Hz, 2H), 7.45 (dd, J=2.1, 6.7 Hz, 2H), 6.99 (dd, J=2.2, 6.7Hz, 2H), 3.87-3.82 (m, 2H), 3.27-3.25 (m, 1H), 3.21 (s, 3H), 2.82-2.75(m, 2H), 1.73-1.69 (m, 2H), 1.59-1.54 (m, 2H);

LC/MS (Method A): 480/482 (M+H), Rt. 5.52 min, purity 95%.

32.24-{4-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-benzoyl}-piperidine-1-carboxylicacid {4-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-phenyl}-methyl-amide(“A32”)

The compound is prepared analogously to example 29 from4-(4-bromo-benzoyl)-piperidine-1-carboxylic acid(4-bromo-phenyl)-methyl-amide (100.0 mg, 0.20 mmol),1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(169.6 mg, 0.44 mmol), cesium carbonate (391.9 mg, 1.19 mmol) and1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane (3.3 mg) in dioxane/water.

Purification: preparative HPLC; yield: 21 mg (17%);

¹H NMR (400 MHz, DMSO-d₆): δ 8.29 (s, 1H), 8.12 (s, 1H), 7.99 (s, 1H),7.92 (dd, J=8.4 Hz, 2H), 7.86 (s, 1H), 7.68 (dd, J=8.3 Hz, 2H), 7.55(dd, J=8.5 Hz, 2H), 7.10 (dd, J=8.5 Hz, 2H), 4.26 (q, J=5.4 Hz, 4H),3.76-3.69 (m, 6H), 3.54-3.49 (m, 1H), 3.23 (s, 3H), 3.22 (s, 3H), 3.09(s, 3H), 2.78 (t, J=12.08 Hz, 2H), 1.63-1.60 (m, 2H), 1.38-1.28 (m, 2H);

LC/MS (Method A): 571.3 (M+H), Rt. 3.96 min, purity 93%.

Example 334-[4-(1-ethyl-1H-pyrazol-4-yl)-benzoyl]-piperidine-1-carboxylic acid(4-methoxy-phenyl)-methyl-amide (“A33”)

The compound is prepared analogously to example 29 from4-(4-bromo-benzoyl)-piperidine-1-carboxylic acid(4-methoxy-phenyl)-methyl-amide (150.0 mg; 0.33 mmol),1-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(139.3 mg, 0.39 mmol), cesium carbonate (324.2 mg, 0.99 mmol) and1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane (27.6 mg, 0.03 mmol) in dioxane/water.

Purification: Column chromatography using silica gel (230-400) andDCM/methanol as gradient elution; yield: 19 mg (12%),

¹H NMR (400 MHz, DMSO-d₆): δ 8.33 (s, 1H), 7.98 (s, 1H), 7.91 (d, J=8.2Hz, 2H), 7.68 (d, J=8.2 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 6.92 (d, J=8.7Hz, 2H), 4.15 (t, J=7.2 Hz, 2H), 3.73-3.70 (m, 5H), 3.51-3.46 (m, 1H),3.01 (s, 3H), 2.75-2.69 (m, 2H), 1.59-1.56 (m, 2H), 1.39 (t, J=7.36 Hz,3H), 1.31-1.24 (m, 2H);

LC/MS (Method A): 447.3 (M+H), Rt. 4.38 min, purity 96%.

Example 34 4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid[4-(1-ethyl-1H-pyrazol-4-yl)-phenyl]-methyl-amide (“A34”)

The compound is prepared analogously to example 29 from4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid(4-bromo-phenyl)-methyl-amide (150.0 mg, 0.34 mmol),1-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(143.6 mg, 0.41 mmol), cesium carbonate (334.1 mg, 1.02 mmol) and1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane (28.5 mg, 0.03 mmol) in dioxane/water.

Purification: Column chromatography using silica gel (230-400) andDCM/methanol as gradient elution; yield: 52 mg (32%);

¹H NMR (400 MHz, DMSO-d₆): δ 8.15 (s, 1H), 7.92 (d, J=8.7 Hz, 2H), 7.83(s, 1H), 7.54 (d, J=8.3 Hz, 2H), 7.10 (d, J=8.3 Hz, 2H), 7.00 (d, J=8.7Hz, 2H), 4.13 (q, J=7.3 Hz, 2H), 3.81 (s, 3H), 3.75-3.72 (m, 2H),3.49-3.46 (m, 1H), 3.08 (s, 3H), 2.79-2.73 (m, 2H), 1.59-1.56 (m, 2H),1.39 (t, J=7.28 Hz, 3H), 1.36-1.32 (m, 2H);

LC/MS (Method A): 447.3 (M+H), Rt. 4.31 min, purity 96%.

Example 354-{4-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-benzoyl}-piperidine-1-carboxylicacid (4-methoxy-phenyl)-methyl-amide (“A35”)

The compound is prepared analogously to example 29 from4-(4-bromo-benzoyl)-piperidine-1-carboxylic acid(4-methoxy-phenyl)-methyl-amide (150.0 mg, 0.33 mmol),1-(2-pyrrolidin-1-yl-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(118.0 mg, 0.39 mmol), cesium carbonate (324.2 mg, 0.99 mmol) and1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complexwith dichloromethane (27.6 mg, 0.03 mmol) in dioxane/water.Purification: preparative HPLC; yield: 16 mg (9%);

¹H NMR (400 MHz, DMSO-d₆): δ 8.33 (s, 1H), 7.98 (s, 1H), 7.91 (d, J=8.3Hz, 2H), 7.68 (d, J=8.2 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.7Hz, 2H), 4.22 (t, J=6.4 Hz, 2H), 3.73-3.70 (m, 5H), 3.55-3.45 (m, 1H),3.01 (s, 3H), 2.83 (t, J=6.60 Hz, 2H), 2.76-2.66 (m, 2H), 2.49-2.45 (m,4H), 1.65-1.63 (m, 4H), 1.59-1.56 (m, 2H), 1.30-1.22 (m, 2H);

LC/MS (Method A): 516 (M+H), Rt. 3.48 min, purity 97%.

Example 36 4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acidmethyl-{4-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-phenyl}-amide(“A36”)

The compound is prepared analogously to example 29 from4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid(4-bromo-phenyl)-methyl-amide (150.0 mg, 0.34 mmol),1-(2-pyrrolidin-1-yl-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(121.6 mg, 0.41 mmol), cesium carbonate (334.1 mg, 1.02 mmol) and1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane (28.5 mg, 0.03 mmol) in dioxane/water.

Purification: Column chromatography using silica gel (230-400) andDCM/methanol as gradient elution; yield: 30 mg (16%);

¹H NMR (400 MHz, DMSO-d₆): δ 8.16 (s, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.84(s, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.5 Hz, 2H), 7.00 (d, J=8.8Hz, 2H), 4.20 (t, J=6.5 Hz, 2H), 3.81 (s, 3H), 3.75-3.72 (m, 2H),3.50-3.43 (m, 1H), 3.08 (s, 3H), 2.84 (t, J=6.44 Hz, 2H), 2.79-2.73 (m,2H), 2.49-2.45 (m, 4H), 1.65-1.57 (m, 6H), 1.36-1.29 (m, 2H);

LC/MS (Method A): 516.3 (M+H), Rt. 3.46 min, purity 95%.

Example 374-{4-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-benzoyl}-piperidine-1-carboxylicacidmethyl-{4-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-phenyl}-amide(“A37”)

The compound is prepared analogously to example 29 from4-(4-bromo-benzoyl)-piperidine-1-carboxylic acid(4-bromo-phenyl)-methyl-amide (100.0 mg, 0.20 mmol),1-(2-pyrrolidin-1-yl-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(130.8 mg, 0.44 mmol), cesium carbonate (391.9 mg, 1.19 mmol) and1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane (33.4 mg, 0.04 mmol) in dioxane/water. Purification:preparative HPLC; yield: 6 mg (5%);

¹H NMR (400 MHz, DMSO-d₆): δ 8.33 (s, 1H), 8.16 (s, 1H), 7.97 (s, 1H),7.92 (d, J=8.4 Hz, 2H), 7.84 (s, 1H), 7.67 (d, J=8.3 Hz, 2H), 7.54 (d,J=8.4 Hz, 2H), 7.10 (d, J=8.5 Hz, 2H), 4.21 (dd, J=6.4, 12.9 Hz, 4H),3.76-3.73 (m, 2H), 3.54-3.48 (m, 1H), 3.08 (s, 3H), 2.84-2.75 (m, 6H),2.49-2.44 (m, 8H), 1.65-1.60 (m, 10H), 1.36-1.31 (m, 2H);

LC/MS (Method A): 649.3 (M+H), Rt. 2.84 min, purity 95%.

The following compounds are prepared analogously

4-(4-methanesulfonylamino-benzoyl)-piperidine-1-carboxylic acidmethyl-phenyl-amide (“A38”)

[(4-benzoyl-piperidine-1-carbonyl)-phenyl-amino]-acetic acid ethyl ester(“A39”)

{[4-(4-methoxy-benzoyl)-piperidine-1-carbonyl]-phenyl-amino}-acetic acidethyl ester (“A40”)

N-ethyl-4-(3-fluoro-4-methoxy-benzoyl)-N-(4-methoxyphenyl)piperidine-1-carboxamide(“A41”)

4-(3-fluoro-4-methoxy-benzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide(“A42”)

¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (t, J=0.32 Hz, 1H), 7.83-7.80 (m, 1H),7.76 (dd, J=2.08, 12.32 Hz, 1H), 7.57 (dd, J=2.88, 8.80 Hz, 1H), 7.26(t, J=8.60 Hz, 1H), 6.82 (d, J=8.88 Hz, 1H), 3.91 (s, 3H), 3.82 (s, 3H),3.67 (d, J=13.12 Hz, 2H), 3.51-3.45 (m, 1H), 3.04 (s, 3H), 2.79-2.72 (m,2H), 1.58 (d, J=10.96 Hz, 2H), 1.30-1.20 (m, 2H); LC/MS (Method A): 402(M+H), Rt. 3.80 min;

N-ethyl-N-(4-methoxyphenyl)-4-(6-methoxypyridine-3-carbonyl)piperidine-1-carboxamide(“A43”)

¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (d, J=2.04 Hz, 1H), 8.15 (dd, J=2.48,8.78 Hz, 1H), 7.04 (dd, J=2.40, 6.74 Hz, 2H), 6.93-6.88 (m, 3H), 3.91(s, 3H), 3.73 (s, 3H), 3.69-3.65 (m, 1H), 3.50-3.40 (m, 1H), 3.48 (t,J=7.04 Hz, 2H), 3.40-3.30 (m, 1H), 2.66 (q, J=6.52 Hz, 2H), 1.56-1.53(m, 2H), 1.27-1.17 (m, 2H), 0.97 (t, J=7.00 Hz, 3H).

LC/MS (Method A): 398 (M+H), Rt. 4.36 min;

4-benzoyl-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide(“A44”)

¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (t, J=0.40 Hz, 1H), 7.94-7.92 (m, 2H),7.64-7.55 (m, 2H), 7.52-7.48 (m, 2H), 6.82 (dd, J=0.44, 8.86 Hz, 1H),3.82 (s, 3H), 3.73-3.64 (m, 2H), 3.56-3.31 (m, 1H), 3.04 (s, 3H),2.80-2.73 (m, 2H), 1.61 (d, J=10.84 Hz, 2H), 1.32-1.21 (m, 2H); LC/MS(Method A): 354 (M+H), Rt. 3.84 min;

N-(6-methoxy-3-pyridyl)-N-methyl-4-(3-methylbenzoyl)piperidine-1-carboxamide(“A45”)

¹H NMR (400 MHz, DMSO-d₆) δ 7.99 (d, J=2.68 Hz, 1H), 7.73 (d, J=7.28 Hz,2H), 7.57 (dd, J=2.84, 8.84 Hz, 1H), 7.44-7.38 (m, 2H), 6.83 (d, J=8.76Hz, 1H), 3.82 (s, 3H), 3.67 (d, J=12.84 Hz, 2H), 3.51 (s, 1H), 3.04 (s,3H), 2.76 (t, J=10.96 Hz, 2H), 2.35 (s, 3H), 1.60 (d, J=10.88 Hz, 2H),1.26 (q, J=3.92 Hz, 2H);

LC/MS (Method A): 368 (M+H), Rt. 4.21 min;

N-(6-methoxy-3-pyridyl)-N-methyl-4-(4-methylbenzoyl)piperidine-1-carboxamide(“A46”)

¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (d, J=2.76 Hz, 1H), 7.84 (d, J=8.20 Hz,2H), 7.57 (dd, J=2.84, 8.80 Hz, 1H), 7.30 (d, J=8.16 Hz, 2H), 6.82 (d,J=8.80 Hz, 1H), 3.82 (s, 3H), 3.67 (d, J=13.12 Hz, 2H), 3.51-3.46 (m,1H), 3.04 (s, 3H), 2.77 (t, J=1.32 Hz, 2H), 2.35 (s, 3H), 1.59 (d,J=11.16 Hz, 2H), 1.31-1.20 (m, 2H); LC/MS (Method A): 368 (M+H), Rt.4.18 min;

4-(3-methoxybenzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide(“A47”)

¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (d, J=2.76 Hz, 1H), 7.58-7.53 (m, 2H),7.44-7.39 (m, 2H), 7.20-7.18 (m, 1H), 6.82 (d, J=8.76 Hz, 1H), 3.82 (s,3H), 3.81 (s, 3H), 3.79-3.65 (m, 2H), 3.54-3.49 (m, 1H), 3.04 (s, 3H),2.79-2.74 (m, 2H), 1.60 (d, J=10.96 Hz, 2H), 1.31-1.21 (m, 2H);

LC/MS (Method A): 384 (M+H), Rt. 3.96 min;

4-[4-(1-ethylpyrazol-4-yl)benzoyl]-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide(“A48”)

¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (s, 1H), 7.99 (t, J=0.40 Hz, 2H), 7.92(d, J=8.48 Hz, 2H), 7.69 (s, 2H), 7.58 (dd, J=2.84, 8.82 Hz, 1H), 6.83(d, J=8.88 Hz, 1H), 4.15 (q, J=7.28 Hz, 2H), 3.83 (s, 3H), 3.68 (d,J=13.00 Hz, 2H), 3.55-3.49 (m, 1H), 3.05 (s, 3H), 2.77 (t, J=10.84 Hz,2H), 1.61 (d, J=10.80 Hz, 2H), 1.40 (t, J=7.28 Hz, 3H), 1.33-1.23 (m,2H); LC/MS (Method A): 448 (M+H), Rt. 3.81 min;

4-(4-methoxybenzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide(“A49”)

¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (d, J=2.56 Hz, 1H), 7.92 (dd, J=1.96,6.96 Hz, 2H), 7.57 (dd, J=2.88, 8.82 Hz, 1H), 7.01 (dd, J=1.88, 7.02 Hz,2H), 6.83 (d, J=8.64 Hz, 1H), 3.82 (s, 6H), 3.37 (d, J=16.7 Hz, 2H),3.66-3.43 (m, 1H), 3.04 (s, 3H), 2.78-2.73 (m, 2H), 1.58 (d, J=11.04 Hz,2H), 1.31-1.21 (m, 2H); LC/MS (Method A): 384 (M+H), Rt. 3.71 min;

4-(3-fluorobenzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide(“A50”)

¹H NMR (400 MHz, DMSO-d₆) δ 7.99 (d, J=2.80 Hz, 1H), 7.79 (d, J=7.68 Hz,1H), 7.72 (d, J=9.72 Hz, 1H), 7.59-7.54 (m, 2H), 7.50-7.46 (m, 1H), 6.83(d, J=8.80 Hz, 1H), 3.82 (s, 3H), 3.69 (t, J=13.16 Hz, 2H), 3.55-3.50(m, 1H), 3.04 (s, 3H), 2.76 (t, J=11.40 Hz, 2H), 1.62 (d, J=11.20 Hz,2H), 1.30-1.20 (m, 2H); LC/MS (Method A): 372 (M+H), Rt. 4.04 min;

4-(4-fluorobenzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide(“A51”)

¹H NMR (400 MHz, DMSO-d₆) δ 8.05-7.98 (m, 3H), 7.57 (dd, J=2.84, 8.80Hz, 1H), 7.35-7.31 (m, 2H), 6.83 (d, J=8.80 Hz, 1H), 3.82 (s, 3H), 3.67(d, J=13.16 Hz, 2H), 3.54-3.48 (m, 1H), 3.04 (s, 3H), 2.78-2.73 (m, 2H),1.60 (d, J=11.20 Hz, 2H), 1.31-1.22 (m, 2H); LC/MS (Method A): 372(M+H), Rt. 3.99 min;

4-(4-methoxy-3-methyl-benzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide(“A52”)

¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (d, J=2.36 Hz, 1H), 7.82 (dd, J=2.20,8.60 Hz, 1H), 7.74 (d, J=1.52 Hz, 1H), 7.58-7.55 (m, 1H), 7.01 (d,J=8.68 Hz, 1H), 6.82 (dd, J=0.40, 8.84 Hz, 1H), 3.85 (s, 3H), 3.82 (s,3H), 3.67 (d, J=13.20 Hz, 2H), 3.49-3.41 (m, 1H), 3.04 (s, 3H), 2.75 (t,J=10.76 Hz, 2H), 2.16 (s, 3H), 1.57 (d, J=10.84 Hz, 2H), 1.31-1.16 (m,2H); LC/MS (Method A): 398 (M+H), Rt. 4.25 min;

N-(4-methoxyphenyl)-4-(6-methoxypyridine-3-carbonyl)-N-methyl-piperidine-1-carboxamide(“A53”)

¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (d, J=2.08 Hz, 1H), 8.16 (dd, J=2.48,8.76 Hz, 1H), 7.06 (dd, J=2.28, 6.70 Hz, 2H), 6.92-6.89 (m, 3H), 3.91(s, 3H), 3.72-3.68 (m, 5H), 3.68-3.41 (m, 1H), 3.01 (s, 3H), 2.73-2.65(m, 2H), 1.58-1.55 (m, 2H), 1.30-1.20 (m, 2H); LC/MS (Method A): 384(M+H), Rt. 4.04 min;

4-[4-(1-Ethyl-1H-pyrazol-4-yl)-benzoyl]-piperidine-1-carboxylic acid[4-(1-ethyl-1H-pyrazol-4-yl)-phenyl]-methyl-amide (“A57”)

¹H NMR (400 MHz, DMSO-d₆) δ 8.33 (s, 1H), 8.15 (s, 1H), 7.97 (s, 1H),7.91 (d, J=8.5 Hz, 2H), 7.83 (s, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.54 (d,J=8.6 Hz, 2H), 7.13-7.09 (m, 2H), 4.17-4.10 (m, 4H), 3.76-3.73 (m, 2H),3.54-3.48 (m, 1H), 3.08 (s, 3H), 2.81-2.75 (m, 2H), 1.62-1.60 (m, 2H),1.41-1.37 (m, 6H), 1.34-1.28 (m, 2H); LC/MS (Method A): 511 (M+H), Rt.4.25 min;

N-(4-cyanophenyl)-4-(4-methoxybenzoyl)-N-methyl-piperidine-1-carboxamide(“A58”)

N-(4-cyanophenyl)-N-(2-hydroxyethyl)-4-(4-methoxybenzoyl)piperidine-1-carboxamide(“A59”)

N-(6-cyano-3-pyridyl)-4-(4-methoxybenzoyl)-N-methyl-piperidine-1-carboxamide(“A60”)

N-(4-cyanophenyl)-4-(3-fluoro-4-methoxy-benzoyl)-N-methyl-piperidine-1-carboxamide(“A61”)

N-(4-cyanophenyl)-N-(2-hydroxyethyl)-4-(4-methoxy-3-methyl-benzoyl)piperidine-1-carboxamide(“A62”)

N-(4-cyanophenyl)-4-(3-fluoro-4-methoxy-benzoyl)-N-(2-hydroxyethyl)piperidine-1-carboxamide(“A63”)

N-(2-hydroxyethyl)-4-(4-methoxybenzoyl)-N-(4-methoxyphenyl)piperidine-1-carboxamide(“A64”)

N-(2-hydroxyethyl)-4-(4-methoxy-3-methyl-benzoyl)-N-(4-methoxyphenyl)piperidine-1-carboxamide(“A65”)

4-(3-fluoro-4-methoxy-benzoyl)-N-(2-hydroxyethyl)-N-(4-methoxyphenyl)piperidine-1-carboxamide(“A66”)

N-(2-hydroxyethyl)-4-(4-methoxy-3-methyl-benzoyl)-N-(6-methoxy-3-pyridyl)piperidine-1-carboxamide(“A67”)

4-(3-fluoro-4-methoxy-benzoyl)-N-(2-hydroxyethyl)-N-(6-methoxy-3-pyridyl)piperidine-1-carboxamide(“A68”)

N-(2-hydroxyethyl)-4-(4-methoxybenzoyl)-N-(6-methoxy-3-pyridyl)piperidine-1-carboxamide(“A69”)

4-(4-methoxybenzoyl)-N-(6-methoxypyridazin-3-yl)-N-methyl-piperidine-1-carboxamide(“A70”)

4-(4-methoxybenzoyl)-N-(2-methoxypyrimidin-5-yl)-N-methyl-piperidine-1-carboxamide(“A71”)

Synthesis of4-[4-(1-hydroxy-1-methyl-ethyl)benzoyl]-N-(4-methoxyphenyl)-N-methyl-piperidine-1-carboxamide(“A54”)

The following compounds are prepared analogously:

N-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-4-(4-methoxybenzoyl)-N-methyl-piperidine-1-carboxamide(“A55”)

4-[4-(1-hydroxy-1-methyl-ethyl)benzoyl]-N-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-N-methyl-piperidine-1-carboxamide(“A56”)

Pharmacological Data

TABLE 1 Inhibition of tankyrases of compounds of the formula I IC₅₀ IC₅₀TNKS1 TNKS2 Compound enzyme enzyme No. assay assay “A1” B B “A2” B B“A3” B B “A4” B B “A5” A B “A6” A B “A7” B B “A8” B B “A9” A B “A10” B C“A11” B B “A12” B B “A13” B B “A14” A B “A15” B B “A16” B B “A17” B B“A18” B B “A19” B B “A20” B B “A21” B B “A22” C C “A23” A B “A24” A B“A25” A B “A26” A B “A27” A B “A28” A A “A29” B “A38” A B “A39” “A40” AB “A41” “A42” A B “A43” “A44” “A45” B B “A46” B B “A47” B B “A48” “A49”A B “A50” B B “A51” B B IC₅₀: <0.3 μM = A 0.3-3 μM = B 3-50 μM = C

TABLE 2 Inhibition of tankyrases of compounds of the formula I EC₅₀ [M]Compound TNKS No. cellular assay “A1” B “A2” B “A3” B “A4” B “A5” A “A6”A “A7” B “A8” A “A9” B “A10” C “A11” B “A12” B “A13” B “A14” A “A15” B“A16” C “A17” B “A18” B “A19” C “A20” C “A21” C “A22” C “A23” A “A24” A“A25” A “A26” A “A27” A “A28” A “A29” A “A30” A “A31” A “A32” A “A33” A“A34” A “A35” A “A36” A “A37” B “A38” B “A39” B “A40” A “A42” A “A43” A“A44” B “A45” A “A46” B “A47” B “A48” B “A49” A “A50” B “A51” B “A52” A“A53” B “A57” A EC₅₀: <0.3 μM = A 0.3-3 μM = B 3-50 μM = C

The compounds shown in Table 2 are particularly preferred compoundsaccording to the invention.

TABLE 3 Inhibition of tankyrases of some representative compounds of theformula I IC₅₀ [M] IC₅₀ [M] Compound IC₅₀ [M] TNKS1 TNKS2 No. PARP ELISAELISA “A1” C A A “A2” C A A “A3” A A “A4” C A A “A5” C A A “A6” C A A“A7” C A A “A8” C A A “A9” A A “A10” B A “A11” A A “A12” A A “A13” C A A“A14” C A A “A15” C A A “A16” C A A “A17” C A A “A18” C A A “A19” A A“A20” A A “A21” B A “A22” B B “A23” A A “A24” C A A “A25” C A A “A26” CA A “A27” C A A “A28” C A A “A29” C A A “A30” C A A “A31” C A A “A32” CA A “A33” C A A “A34” C A A “A35” C A A “A36” C A A “A37” A A “A38” C AA “A39” C A A “A40” C A A “A42” A A “A43” A A “A44” A A “A45” A A “A46”A A “A47” A A “A48” A A “A49” A A “A50” A A “A51” A A “A52” A A “A53” AA “A57” A A IC₅₀: <0.3 μM = A 0.3-3 μM = B 3-50 μM = C

The compounds shown in Table 3 are particularly preferred compoundsaccording to the invention.

The following examples relate to medicaments:

Example A: Injection Vials

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2 N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

Example B: Suppositories

A mixture of 20 g of an active ingredient of the formula I with 100 g ofsoya lecithin and 1400 g of cocoa butter is melted, poured into mouldsand allowed to cool. Each suppository contains 20 mg of activeingredient.

Example C: Solution

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

Example D: Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

Example E: Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active ingredient.

Example F: Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

Example G: Capsules

2 kg of active ingredient of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

Example H: Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

The invention claimed is:
 1. A compound that is No. Name “A1”4-benzoyl-piperidine-1-carboxylic acid methyl-m-tolyl-amide “A2”4-benzoyl-piperidine-1-carboxylic acid methyl-p-tolyl-amide “A3”4-benzoyl-piperidine-1-carboxylic acid (3-methoxy-phenyl)- methyl-amide“A4” 4-benzoyl-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl-amide “A5” 4-(4-methyl-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl-amide “A6”4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl-amide “A7”4-(3-fluoro-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl-amide “A8” 4-(4-fluoro-benzoyl)-piperidine-1-carboxylicacid (4-methoxy- phenyl)-methyl-amide “A9”4-(4-chloro-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl-amide “A10” 4-benzoyl-piperidine-1-carboxylicacid (3-cyano-phenyl)- methyl-amide “A11”4-benzoyl-piperidine-1-carboxylic acid (4-cyano-phenyl)- methyl-amide“A12” 4-benzoyl-piperidine-1-carboxylic acid (3-fluoro-phenyl)-methyl-amide “A13” 4-benzoyl-piperidine-1-carboxylic acid(4-fluoro-phenyl)- methyl-amide “A14” 4-benzoyl-piperidine-1-carboxylicacid ethyl-(4-methoxy- phenyl)-amide “A15”4-benzoyl-piperidine-1-carboxylic acid (2-hydroxy-ethyl)-(4-methoxy-phenyl)-amide “A16”(4-benzoyl-piperidin-1-yl)-(2,3-dihydro-indol-1-yl)-methanone “A17”(2,3-dihydro-indol-1-yl)-[4-(4-methyl-benzoyl)-piperidin-1-yl]-methanone “A18”(2,3-dihydro-indol-1-yl)-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-methanone “A19”(2,3-dihydro-indol-1-yl)-[4-(3-fluoro-benzoyl)-piperidin-1-yl]-methanone “A20”(2,3-dihydro-indol-1-yl)-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-methanone “A21”[4-(4-chloro-benzoyl)-piperidin-1-yl]-(2,3-dihydro-indol-1-yl)-methanone “A22”(4-benzoyl-piperidin-1-yl)-(3,4-dihydro-2H-quinolin-1-yl)- methanone“A23” 4-(4-methoxy-3-methyl-benzoyl)-piperidine-1-carboxylic acid(4-methoxy-phenyl)-methyl-amide “A24”4-(4-methoxy-3-methyl-benzoyl)-piperidine-1-carboxylic acidethyl-(4-methoxy-phenyl)-amide “A25”4-(3-methyl-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl-amide “A26”4-(3-methyl-benzoyl)-piperidine-1-carboxylic acid ethyl-(4-methoxy-phenyl)-amide “A27”4-(3-methoxy-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl-amide “A28”4-(3-methoxy-benzoyl)-piperidine-1-carboxylic acid ethyl-(4-methoxy-phenyl)-amide “A29”4-(3-fluoro-4-methoxy-benzoyl)-piperidine-1-carboxylic acid(4-methoxy-phenyl)-methyl-amide “A30”4-{4-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-benzoyl}-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl- amide “A31”4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid {4-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-phenyl}-methyl-amide “A32”4-{4-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-benzoyl}-piperidine-1-carboxylic acid {4-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-phenyl}-methyl-amide “A33”4-[4-(1-ethyl-1H-pyrazol-4-yl)-benzoyl]-piperidine-1- carboxylic acid(4-methoxy-phenyl)-methyl-amide “A34”4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid [4-(1-ethyl-1H-pyrazol-4-yl)-phenyl]-methyl-amide “A35”4-{4-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-benzoyl}-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl- amide “A36”4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid methyl-{4-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-phenyl}-amide “A37”4-{4-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-benzoyl}-piperidine-1-carboxylic acid methyl-{4-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-phenyl}-amide “A38”4-(4-methanesulfonylamino-benzoyl)-piperidine-1-carboxylic acidmethyl-phenyl-amide “A39”[(4-benzoyl-piperidine-1-carbonyl)-phenyl-amino]-acetic acid ethyl ester“A40” {[4-(4-methoxy-benzoyl)-piperidine-1-carbonyl]-phenyl-amino}-acetic acid ethyl ester “A41”N-ethyl-4-(3-fluoro-4-methoxy-benzoyl)-N-(4-methoxyphenyl)piperidine-1-carboxamide “A42”4-(3-fluoro-4-methoxy-benzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide “A43”N-ethyl-N-(4-methoxyphenyl)-4-(6-methoxypyridine-3-carbonyl)piperidine-1-carboxamide “A44”4-benzoyl-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1- carboxamide“A45” N-(6-methoxy-3-pyridyl)-N-methyl-4-(3-methylbenzoyl)piperidine-1-carboxamide “A46”N-(6-methoxy-3-pyridyl)-N-methyl-4-(4-methylbenzoyl)piperidine-1-carboxamide “A47”4-(3-methoxybenzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide “A48”4-[4-(1-ethylpyrazol-4-yl)benzoyl]-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide “A49”4-(4-methoxybenzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide “A50”4-(3-fluorobenzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide “A51”4-(4-fluorobenzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide “A52”4-(4-methoxy-3-methyl-benzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide “A53”N-(4-methoxyphenyl)-4-(6-methoxypyridine-3-carbonyl)-N-methyl-piperidine-1-carboxamide “A54”4-[4-(1-hydroxy-1-methyl-ethyl)benzoyl]-N-(4-methoxyphenyl)-N-methyl-piperidine-1-carboxamide “A55”N-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-4-(4-methoxybenzoyl)-N-methyl-piperidine-1-carboxamide “A56”4-[4-(1-hydroxy-1-methyl-ethyl)benzoyl]-N-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-N-methyl-piperidine-1-carboxamide “A57”4-[4-(1-Ethyl-1H-pyrazol-4-yl)-benzoyl]-piperidine-1- carboxylic acid[4-(1-ethyl-1H-pyrazol-4-yl)-phenyl]-methyl- amide “A58”N-(4-cyanophenyl)-4-(4-methoxybenzoyl)-N-methyl-piperidine-1-carboxamide “A59”N-(4-cyanophenyl)-N-(2-hydroxyethyl)-4-(4-methoxybenzoyl)piperidine-1-carboxamide “A60”N-(6-cyano-3-pyridyl)-4-(4-methoxybenzoyl)-N-methyl-piperidine-1-carboxamide “A61”N-(4-cyanophenyl)-4-(3-fluoro-4-methoxy-benzoyl)-N-methyl-piperidine-1-carboxamide “A62”N-(4-cyanophenyl)-N-(2-hydroxyethyl)-4-(4-methoxy-3-methyl-benzoyl)piperidine-1-carboxamide “A63”N-(4-cyanophenyl)-4-(3-fluoro-4-methoxy-benzoyl)-N-(2-hydroxyethyl)piperidine-1-carboxamide “A64”N-(2-hydroxyethyl)-4-(4-methoxybenzoyl)-N-(4-methoxyphenyl)piperidine-1-carboxamide “A65”N-(2-hydroxyethyl)-4-(4-methoxy-3-methyl-benzoyl)-N-(4-methoxyphenyl)piperidine-1-carboxamide “A66”4-(3-fluoro-4-methoxy-benzoyl)-N-(2-hydroxyethyl)-N-(4-methoxyphenyl)piperidine-1-carboxamide “A67”N-(2-hydroxyethyl)-4-(4-methoxy-3-methyl-benzoyl)-N-(6-methoxy-3-pyridyl)piperidine-1-carboxamide “A68”4-(3-fluoro-4-methoxy-benzoyl)-N-(2-hydroxyethyl)-N-(6-methoxy-3-pyridyl)piperidine-1-carboxamide “A69”N-(2-hydroxyethyl)-4-(4-methoxybenzoyl)-N-(6-methoxy-3-pyridyl)piperidine-1-carboxamide “A70”4-(4-methoxybenzoyl)-N-(6-methoxypyridazin-3-yl)-N-methyl-piperidine-1-carboxamide “A71”4-(4-methoxybenzoyl)-N-(2-methoxypyrimidin-5-yl)-N-methyl-piperidine-1-carboxamide

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,including mixtures thereof in all ratios.
 2. A pharmaceuticalcomposition comprising at least one compound of claim 1 or apharmaceutically acceptable salt, solvate, tautomer or stereoisomerthereof, including mixtures thereof in all ratios, and apharmaceutically acceptable carrier, excipient or vehicle.
 3. Amedicament comprising at least one compound of claim 1 or apharmaceutically acceptable salt, solvate or stereoisomer thereof,including mixtures thereof in all ratios, and at least one furthermedicament active ingredient.
 4. A kit consisting of separate packs of(a) an effective amount of a compound of claim 1 or a pharmaceuticallyacceptable salt, solvate, salt or stereoisomer thereof, includingmixtures thereof in all ratios, and (b) an effective amount of a furthermedicament active ingredient.